Advertisement

Obesity, Inflammation, and Insulin Resistance

      Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus.

      Abbreviations used in this paper:

      CRP (C-reactive protein), CVD (cardiovascular disease), FFA (free fatty acids), HFD (high-fat diet), IKKβ (inhibitor of NK-kB kinase β), IL-6 (interleukin-6), IRS-1 (insulin receptor substrate-1), JNK (c-Jun NH2-terminal kinase), MCP-1 (monocyte chemoattractant protein-1), NAFLD (nonalcoholic fatty liver disease), PAI-1 (plasminogen activator inhibitor-1), PPARγ (peroxisome proliferator-activated receptor-γ), SAA (serum amyloid A), TNF-α (tumor necrosis factor-α), TZD (thiazolidinedione), T2D (type 2 diabetes mellitus.)
      Mammals have evolved mechanisms to store energy during periods of plenty, which helps to guarantee survival during periods of drought and famine. Excess nutrient is stored as triglyceride, primarily in the adipose tissue but in other tissues as well. In addition to the beneficial effects of nutrient storage, however, the long-term storage of excessive amounts of lipid can have a negative impact on health, especially under conditions of longer life span and decreased physical activity. The adverse health consequences of weight gain and obesity are especially prominent following prolonged periods of positive energy balance and may be most pronounced when foods are energy dense because of high proportions of simple carbohydrates and saturated fats, such as occurs today in developed Western societies. As a consequence of sustained overnutrition, obesity has become epidemic in industrialized countries and is increasingly common in developing countries worldwide. The prevalence rates are continuing to rise, most rapidly in developing countries, and obesity is occurring in all groups at younger ages. The World Health Organization estimates that globally there are >1 billion overweight adults, 300 million of whom are obese.

      World Health Organization. Fact sheet: obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed February 8, 2007.

      Since 1980, obesity rates have risen more than 3-fold in some areas of North America, the United Kingdom, Eastern Europe, the Middle East, the Pacific Islands, Australasia, and China. Very worrisome are the concurrent and parallel increases in the prevalence of pathologic conditions associated with obesity, which include type 2 diabetes mellitus (T2D), cardiovascular disease (CVD), hypertension, hypercholesterolemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), arthritis, asthma, and certain forms of cancer. We review the growing evidence that supports the hypothesis that a subacute state of chronic inflammation associated with obesity provides a molecular link to some of these pathologic conditions.

      Adipose Tissue

      In addition to containing adipocytes, adipose tissue is well vascularized and innervated and contains a connective tissue matrix and numerous immune cells including macrophages.
      • Weisberg S.P.
      • McCann D.
      • Desai M.
      • Rosenbaum M.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      Obesity is associated with macrophage accumulation in adipose tissue.
      • Xu H.
      • Barnes G.T.
      • Yang Q.
      • Tan G.
      • Yang D.
      • Chou C.J.
      • Sole J.
      • Nichols A.
      • Ross J.S.
      • Tartaglia L.A.
      • Chen H.
      Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
      White adipose tissue (WAT) is most familiar as the type of fat in which triglyceride is stored and from which lipids are mobilized for systemic utilization when other tissues require energy. WAT is often subdivided into subcutaneous and abdominal depots, whose physiologies may be distinguished and whose roles in pathology may also be distinct. This is contrasted with brown adipose tissue, whose main function is thought to be nonshivering thermogenesis, a process of heat production through the uncoupling of oxidative phosphorylation. Uncoupling protein-1, an integral membrane protein located in the mitochondrial inner membrane, regulates the thermogenic proton leak in brown adipose tissue.
      • Krauss S.
      • Zhang C.Y.
      • Lowell B.B.
      The mitochondrial uncoupling-protein homologues.
      Originally considered to be a passive depot for energy storage, WAT is now known to secrete a variety of substances that help to regulate metabolic homeostasis. These include leptin, adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, visfatin, retinol-binding protein-4, serum amyloid A (SAA), and others.
      • Fried S.K.
      • Bunkin D.A.
      • Greenberg A.S.
      Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
      • Fukuhara A.
      • Matsuda M.
      • Nishizawa M.
      • Segawa K.
      • Tanaka M.
      • Kishimoto K.
      • Matsuki Y.
      • Murakami M.
      • Ichisaka T.
      • Murakami H.
      • Watanabe E.
      • Takagi T.
      • Akiyoshi M.
      • Ohtsubo T.
      • Kihara S.
      • Yamashita S.
      • Makishima M.
      • Funahashi T.
      • Yamanaka S.
      • Hiramatsu R.
      • Matsuzawa Y.
      • Shimomura I.
      Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.
      • Shimomura I.
      • Funahashi T.
      • Takahashi M.
      • Maeda K.
      • Kotani K.
      • Nakamura T.
      • Yamashita S.
      • Miura M.
      • Fukuda Y.
      • Takemura K.
      • Tokunaga K.
      • Matsuzawa Y.
      Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.
      • Steppan C.M.
      • Bailey S.T.
      • Bhat S.
      • Brown E.J.
      • Banerjee R.R.
      • Wright C.M.
      • Patel H.R.
      • Ahima R.S.
      • Lazar M.A.
      The hormone resistin links obesity to diabetes.
      Leptin and adiponectin are considered to be primary adipocytokines because they appear to be produced primarily by adipocytes. Resistin, however, is produced in humans by mononuclear cells such as macrophages and by both adipocytes and macrophages in rodents.
      • Steppan C.M.
      • Bailey S.T.
      • Bhat S.
      • Brown E.J.
      • Banerjee R.R.
      • Wright C.M.
      • Patel H.R.
      • Ahima R.S.
      • Lazar M.A.
      The hormone resistin links obesity to diabetes.
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      TNF-α, IL-6, MCP-1, visfatin, and PAI-1 are expressed in adipocytes as well as activated macrophages and/or other immune cells. The relative amounts of each produced by the adipocyte versus the macrophages present in the adipose tissue are still unclear. The potential roles of leptin, adiponectin, resistin, and visfatin as mediators linking adipose tissue, inflammation, and immunity has been recently reviewed.
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      Thus, adipose tissue is a complex and active secretory organ that both sends and receives signals that modulate energy expenditure, appetite, insulin sensitivity, endocrine and reproductive functions, bone metabolism, inflammation, and immunity.
      Immune cells in the adipose tissue, specifically macrophages, have increasingly caught the attention of the scientific community. In both humans and mice, the number of bone marrow-derived macrophages correlates with obesity and adipocyte size.
      • Weisberg S.P.
      • McCann D.
      • Desai M.
      • Rosenbaum M.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      Obesity is associated with macrophage accumulation in adipose tissue.
      Adipose tissue in obese subjects is characterized by macrophage infiltration,
      • Weisberg S.P.
      • McCann D.
      • Desai M.
      • Rosenbaum M.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      Obesity is associated with macrophage accumulation in adipose tissue.
      • Xu H.
      • Barnes G.T.
      • Yang Q.
      • Tan G.
      • Yang D.
      • Chou C.J.
      • Sole J.
      • Nichols A.
      • Ross J.S.
      • Tartaglia L.A.
      • Chen H.
      Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
      which has been shown to be stimulated by adipocyte production of the monocyte chemoattractant MCP-1.
      • Kanda H.
      • Tateya S.
      • Tamori Y.
      • Kotani K.
      • Hiasa K.
      • Kitazawa R.
      • Kitazawa S.
      • Miyachi H.
      • Maeda S.
      • Egashira K.
      • Kasuga M.
      MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
      Moreover, adipose tissue-resident macrophages are also a source of proinflammatory factors that may modulate the secretory activity of adipocytes.
      • Xu H.
      • Barnes G.T.
      • Yang Q.
      • Tan G.
      • Yang D.
      • Chou C.J.
      • Sole J.
      • Nichols A.
      • Ross J.S.
      • Tartaglia L.A.
      • Chen H.
      Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
      Both adipocytes and macrophages contribute to WAT-derived IL-6. Abdominal WAT produces higher levels of IL-6 than subcutaneous WAT.
      • Fried S.K.
      • Bunkin D.A.
      • Greenberg A.S.
      Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
      • Fain J.N.
      • Madan A.K.
      • Hiler M.L.
      • Cheema P.
      • Bahouth S.W.
      Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans.
      In fact, there are several ways that subcutaneous visceral adipose tissue depots differ, including by cell size,
      • Johnson P.R.
      • Hirsch J.
      Cellularity of adipose depots in six strains of genetically obese mice.
      • Krotkiewski M.
      • Bjorntorp P.
      • Sjostrom L.
      • Smith U.
      Impact of obesity on metabolism in men and women Importance of regional adipose tissue distribution.
      metabolic activity, and potential role in insulin resistance.
      • Coon P.J.
      • Rogus E.M.
      • Drinkwater D.
      • Muller D.C.
      • Goldberg A.P.
      Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.
      • Gastaldelli A.
      • Miyazaki Y.
      • Pettiti M.
      • Matsuda M.
      • Mahankali S.
      • Santini E.
      • DeFronzo R.A.
      • Ferrannini E.
      Metabolic effects of visceral fat accumulation in type 2 diabetes.
      Visceral adiposity, rather than simply a high body mass index (BMI), correlates best with increased risk of CVD and diabetes, although the biochemical and physiologic reasons for this are still unclear. One possible explanation is that visceral but not subcutaneous WAT has direct access to the portal circulation so that substances produced by visceral fat may directly impact the liver.

      Liver

      The specialized anatomy of the liver provides a mechanism for the portal and arterial circulations to interact with both liver parenchyma (hepatocytes) and the many immune cells also located within the liver. The hepatocytes represent approximately two thirds of the total cells in liver. The remaining cells are diverse and include biliary epithelial cells, sinusoidal endothelial cells, Kupffer cells (resident macrophages), stellate cells (also called Ito or fat-storage cells), dendritic cells, and several types of lymphocytes
      • Racanelli V.
      • Rehermann B.
      The liver as an immunological organ.
      (Figure 1). Blood from the gastrointestinal tract travels via the afferent portal vein to the hepatic sinusoids in which it interacts with the sinusoidal endothelial cells and hepatic immune cells on its way to the efferent central veins. The sinusoidal endothelial cells represent approximately 50% of the nonparenchymal cells. Unlike endothelial cells in many organs, the sinusoidal endothelial cells form a sieve-like, fenestrated epithelium and participate in antigen presentation. The Kupffer cells and lymphocytes account for the bulk of immune cells in liver. Kupffer cells occupy the sinusoidal space where they phagocytose microorganisms and other debris. The lymphocytes are largely T cells and natural killer (NK) cells, with B cells making up a much smaller percentage. NKT cells account for up to 30% of the total lymphocytes in liver, which is a higher percentage than is typically found in other organs.
      Figure thumbnail gr1
      Figure 1Potential mechanisms for inflammation-induced injury in NAFLD. Multiple cell types within the hepatic sinusoid, including hepatocytes, endothelial cells, hepatic stellate cells (HSC), resident macrophages (Kupffer cells), B and T lymphocytes, NK cells, NKT cells and dentritic cells (DCs), may contribute to the inflammatory processes that accompany steatosis. Stellate cells are often found in the subendothelial space of Disse. The immune cells including the Kupffer cells line the sinusoid lumen. The portal delivery of lipids and proinflammatory cytokines as well as locally generated inflammatory mediators and reactive oxygen species may promote both inflammatory and fibrotic processes associated with the progression of NAFLD.
      The accumulation of lipid in the liver often accompanies and parallels weight gain and obesity. Hepatic steatosis, the accumulation of lipid in the hepatocytes, has negative effects on liver function, which may also be mediated by inflammation. For example, messenger RNA (mRNA) expression of proinflammatory cytokines including IL-6, TNF-α, and IL-1β increases in liver with increasing adiposity.
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • Melendez P.A.
      • Hansen L.
      • Lee J.
      • Shoelson S.E.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.
      This suggests that steatosis might induce a subacute inflammatory response in liver similar to that seen with the accumulation of lipid into the adipocytes. As an additional or alternative possibility, proinflammatory cytokines and lipids and other substances produced in the abdominal fat and carried to the liver through the portal circulation could contribute to hepatic inflammation. Proinflammatory substances activate the Kupffer cells, which are abundant in the liver and account for over 5% of total cells. The activation state of Kupffer cells but not their number increases with obesity.
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • Melendez P.A.
      • Hansen L.
      • Lee J.
      • Shoelson S.E.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.
      The many additional immune cell types in liver may also play roles in inflammation-induced insulin resistance. For example, the number of NKT cells is selectively reduced in the steatotic livers of obese, leptin-deficient ob/ob mice or high-fat diet (HFD)-treated mice.
      • Guebre-Xabier M.
      • Yang S.
      • Lin H.Z.
      • Schwenk R.
      • Krzych U.
      • Diehl A.M.
      Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage.
      • Li Z.
      • Soloski M.J.
      • Diehl A.M.
      Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.
      Given that NKT cells have regulatory roles in immune function,
      • Godfrey D.I.
      • Kronenberg M.
      Going both ways: immune regulation via CD1d-dependent NKT cells.
      such significant changes in number could have substantial ramifications in terms of both physiology and pathology. Interestingly, adoptive transfer of NKT cells into ob/ob mice resulted in a reduction of the hepatic fat content, steatosis, and improvement in glucose intolerance.
      • Elinav E.
      • Pappo O.
      • Sklair-Levy M.
      • Margalit M.
      • Shibolet O.
      • Gomori M.
      • Alper R.
      • Thalenfeld B.
      • Engelhardt D.
      • Rabbani E.
      • Ilan Y.
      Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping.

      Obesity as a Proinflammatory State

      Epidemiologic evidence for links between obesity and inflammation have existed for decades, although these findings were not appreciated in terms of the pathophysiologic conditions associated with obesity. For example, the levels of circulating fibrinogen and other acute phase reactants were found to be elevated in obesity.
      • Fearnley G.R.
      • Vincent C.T.
      • Chakrabarti R.
      Reduction of blood fibrinolytic activity in diabetes mellitus by insulin.
      • Grace C.S.
      • Goldrick R.B.
      Fibrinolysis and body bulid Interrelationships between blood fibrinolysis, body composition and parameters of lipid and carbohydrate metabolism.
      • Ogston D.
      • McAndrew G.M.
      Fibrinolysis in obesity.
      More recent epidemiologic studies have confirmed and extended these earlier findings by showing increases of additional acute phase reactants in obese subjects, including TNF-α, IL-6, and C-reactive protein (CRP).
      • Dandona P.
      • Aljada A.
      • Bandyopadhyay A.
      Inflammation: the link between insulin resistance, obesity and diabetes.
      • Kern P.A.
      • Ranganathan S.
      • Li C.
      • Wood L.
      • Ranganathan G.
      Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.
      • Dandona P.
      • Weinstock R.
      • Thusu K.
      • Abdel-Rahman E.
      • Aljada A.
      • Wadden T.
      Tumor necrosis factor-α in sera of obese patients: fall with weight loss.
      • Vozarova B.
      • Weyer C.
      • Hanson K.
      • Tataranni P.A.
      • Bogardus C.
      • Pratley R.E.
      Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion.
      • Wakabayashi I.
      Age-related change in relationship between body-mass index, serum sialic acid, and atherogenic risk factors.
      • Pradhan A.D.
      • Manson J.E.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
      The direct effects of TNF-α on adipocyte insulin resistance provided a more direct link to potential pathogenic mechanisms.
      • Hotamisligil G.S.
      • Shargill N.S.
      • Spiegelman B.M.
      Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.
      • Feinstein R.
      • Kanety H.
      • Papa M.Z.
      • Lunenfeld B.
      • Karasik A.
      Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.
      Growing evidence suggests that macronutrient intake and obesity may both activate inflammatory signaling pathways in cells. Glucose and fat intake have both been shown to induce inflammation, potentially through increases in oxidative stress
      • Mohanty P.
      • Ghanim H.
      • Hamouda W.
      • Aljada A.
      • Garg R.
      • Dandona P.
      Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.
      and the activities of transcription factors including nuclear factor (NF)-κB,
      • Dhindsa S.
      • Tripathy D.
      • Mohanty P.
      • Ghanim H.
      • Syed T.
      • Aljada A.
      • Dandona P.
      Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-κB in mononuclear cells.
      activating protein-1, and early growth response-1.
      • Aljada A.
      • Ghanim H.
      • Mohanty P.
      • Syed T.
      • Bandyopadhyay A.
      • Dandona P.
      Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations.
      Intravenous lipid infusion (triglyceride plus heparin) in normal subjects can be used to raise levels of free fatty acids (FFA) to those seen in obese subjects, which leads to an inflammatory response.
      • Tripathy D.
      • Mohanty P.
      • Dhindsa S.
      • Syed T.
      • Ghanim H.
      • Aljada A.
      • Dandona P.
      Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects.
      Consistent with this, reductions in macronutrient intake in obese individuals, as seen with caloric restriction to 1000 kcal/day for 4 weeks
      • Dandona P.
      • Mohanty P.
      • Ghanim H.
      • Aljada A.
      • Browne R.
      • Hamouda W.
      • Prabhala A.
      • Afzal A.
      • Garg R.
      The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation.
      or a 48-hour fast,
      • Dandona P.
      • Mohanty P.
      • Hamouda W.
      • Ghanim H.
      • Aljada A.
      • Garg R.
      • Kumar V.
      Inhibitory effect of a two-day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations.
      lead to reduced oxidative stress and inflammatory mediators.
      Dietary excess and obesity are associated with the accumulation of lipid into adipocytes and the expansion of the adipose tissue (Figure 2). Hypertrophic adipocytes may produce proinflammatory cytokines such as TNF-α, IL-6, resistin, MCP-1, and PAI-1 (Figure 3). The production of these substances undoubtedly has local effects, including on the endothelium leading to up-regulated adhesion molecule synthesis (eg, intracellular adhesion molecule and vascular cell adhesion molecule) and increased vascular permeability, and on circulating monocytes, which are recruited by chemokines including MCP-1.
      • Weisberg S.P.
      • Hunter D.
      • Huber R.
      • Lemieux J.
      • Slaymaker S.
      • Vaddi K.
      • Charo I.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
      The inflammatory signal is enhanced by the cross talk among endothelial cells, adipocytes, and resident macrophages, which together contribute to the production of proinflammatory cytokines and induce a state of local and systemic insulin resistance. This is consistent with reports of increased expression of proinflammatory genes by macrophages in the adipose tissue of obese mice followed by exaggerated increases in circulating insulin.
      • Xu H.
      • Barnes G.T.
      • Yang Q.
      • Tan G.
      • Yang D.
      • Chou C.J.
      • Sole J.
      • Nichols A.
      • Ross J.S.
      • Tartaglia L.A.
      • Chen H.
      Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
      It is thus possible that the accumulation of lipids in adipocytes initiates the inflammatory signal in adipose tissue and that resident macrophages serve to amplify the signal.
      Figure thumbnail gr2
      Figure 2Adipose tissue inflammation. H&E-stained sections are shown from the epididymal adipose tissue of 14-week-old (A) wt C57Bl/6 mice and (B) obese ob/ob mice. The increase in fat cell size seen in ob/ob mice is accompanied by the increased infiltration of immune cells including macrophages (arrows).
      Figure thumbnail gr3
      Figure 3Potential mechanisms for obesity-induced inflammation. The accumulation of lipids in adipose tissue and the expansion of the fat mass lead to the initiation of an inflammatory process. This may be initiated through the production of proinflammatory cytokines and chemokines by the adipocytes, including TNF-α, IL-6, leptin, resistin, MCP-1, and PAI-1. Endothelial cells respond through the increased expression of adhesion molecules, which along with the chemokines serve to recruit immune cells including monocyte-derived macrophages to the adipose tissue. Together, the adipocyte-, immune cell-, and endothelial cell-derived substances create an inflammatory milieu that promotes insulin resistance locally. Similar proinflammatory and proatherogenic mediators enter the circulation to promote insulin resistance and increase risk for atherosclerosis.

      Potential Mechanisms for Inflammation-Induced Insulin Resistance

      Two transcription factor-signaling pathways have been linked to the proinflammatory effects of obesity and insulin resistance: the NF-κB pathway, which is activated by inhibitor of NF-κB (IκB) kinase β (IKKβ), and the c-Jun NH2-terminal kinase (JNK) pathway. These pathways are activated by many of the same proinflammatory stimuli including cytokines such as TNF-α, which in addition to being activators of NF-κB are also NF-κB-regulated products. Both pathways are also activated by pattern recognition receptors, such as the receptor for advanced glycation end products and the toll-like receptors, which are gatekeepers of the innate immune system. In addition to being activated by bacterial, viral, and fungal products, toll-like receptors can be activated by fatty acids,
      • Lee J.Y.
      • Sohn K.H.
      • Rhee S.H.
      • Hwang D.
      Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.
      • Shi H.
      • Kokoeva M.V.
      • Inouye K.
      • Tzameli I.
      • Yin H.
      • Flier J.S.
      TLR4 links innate immunity and fatty acid-induced insulin resistance.
      which suggests a potential link between elevated circulating or tissue lipid concentrations and the immune system. Reactive oxygen species, endoplasmic reticulum stress, and ceramides are increased by adiposity, and all have also been shown to activate both JNK and NF-κB.
      • Furukawa S.
      • Fujita T.
      • Shimabukuro M.
      • Iwaki M.
      • Yamada Y.
      • Nakajima Y.
      • Nakayama O.
      • Makishima M.
      • Matsuda M.
      • Shimomura I.
      Increased oxidative stress in obesity and its impact on metabolic syndrome.
      • Ozcan U.
      • Cao Q.
      • Yilmaz E.
      • Lee A.H.
      • Iwakoshi N.N.
      • Ozdelen E.
      • Tuncman G.
      • Gorgun C.
      • Glimcher L.H.
      • Hotamisligil G.S.
      Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.
      • Summers S.A.
      Ceramides in insulin resistance and lipotoxicity.
      In addition, FFA increase the activities of various protein kinase C isoforms, which can in turn activate IKK and JNK.
      • Gao Z.
      • Zhang X.
      • Zuberi A.
      • Hwang D.
      • Quon M.J.
      • Lefevre M.
      • Ye J.
      Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.
      More information about the molecular links between inflammation and insulin resistance can be found in recently published reviews.
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      • Shoelson S.E.
      • Lee J.
      • Goldfine A.B.
      Inflammation and insulin resistance.
      Consistent with the findings described above, genetic disruption of NF-κB and JNK signaling pathways has been shown to improve insulin resistance. Heterozygous IKKβ+/− mice, fed with an HFD or crossed with obese ob/ob mice, were protected against the development of insulin resistance.
      • Yuan M.
      • Konstantopoulos N.
      • Lee J.
      • Hansen L.
      • Li Z.W.
      • Karin M.
      • Shoelson S.E.
      Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.
      Moreover, inhibition of NF-κB in macrophages or liver, through the tissue-specific expression of dominant inhibitory IκBα or tissue-specific deletion of IKKβ, attenuates inflammatory gene expression and insulin resistance in response to HFD (Table 1).
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • Melendez P.A.
      • Hansen L.
      • Lee J.
      • Shoelson S.E.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.
      • Arkan M.C.
      • Hevener A.L.
      • Greten F.R.
      • Maeda S.
      • Li Z.W.
      • Long J.M.
      • Wynshaw-Boris A.
      • Poli G.
      • Olefsky J.
      • Karin M.
      IKK-β links inflammation to obesity-induced insulin resistance.
      Pharmacologic inhibition with salicylates, presumably through the targeting of IKKβ/NF-κB, has proved to improve insulin resistance in obese mice models such as HFD-treated mice and ob/ob mice.
      • Yuan M.
      • Konstantopoulos N.
      • Lee J.
      • Hansen L.
      • Li Z.W.
      • Karin M.
      • Shoelson S.E.
      Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.
      • Hundal R.S.
      • Petersen K.F.
      • Mayerson A.B.
      • Randhawa P.S.
      • Inzucchi S.
      • Shoelson S.E.
      • Shulman G.I.
      Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
      • Shoelson S.E.
      • Lee J.
      • Yuan M.
      Inflammation and the IKK β/IκB/NF-κB axis in obesity- and diet-induced insulin resistance.
      JNK1 knockout mice are also protected against diet-induced or genetically induced (ob/ob) insulin resistance,
      • Hirosumi J.
      • Tuncman G.
      • Chang L.
      • Gorgun C.Z.
      • Uysal K.T.
      • Maeda K.
      • Karin M.
      • Hotamisligil G.S.
      A central role for JNK in obesity and insulin resistance.
      and inhibitors of JNK also appear to improve insulin sensitivity in insulin resistant mice (Table 1).
      • Kaneto H.
      • Nakatani Y.
      • Miyatsuka T.
      • Kawamori D.
      • Matsuoka T.A.
      • Matsuhisa M.
      • Kajimoto Y.
      • Ichijo H.
      • Yamasaki Y.
      • Hori M.
      Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide.
      Table 1Knockout Mice With Potentially Relevant Metabolic Phenotypes
      GenePhenotype
      IL-6Mature onset obesity and insulin resistance
      • Wallenius V.
      • Wallenius K.
      • Ahren B.
      • Rudling M.
      • Carlsten H.
      • Dickson S.L.
      • Ohlsson C.
      • Jansson J.O.
      Interleukin-6-deficient mice develop mature-onset obesity.
      TNF-αImproved insulin sensitivity and insulin signalling
      • Uysal K.T.
      • Wiesbrock S.M.
      • Marino M.W.
      • Hotamisligil G.S.
      Protection from obesity-induced insulin resistance in mice lacking TNF-α function.
      PAI-1Improved insulin sensitivity
      • Ma L.J.
      • Mao S.L.
      • Taylor K.L.
      • Kanjanabuch T.
      • Guan Y.
      • Zhang Y.
      • Brown N.J.
      • Swift L.L.
      • McGuinness O.P.
      • Wasserman D.H.
      • Vaughan D.E.
      • Fogo A.B.
      Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
      IL-18Hyperphagia, obesity, and insulin resistance
      • Netea M.G.
      • Joosten L.A.
      • Lewis E.
      • Jensen D.R.
      • Voshol P.J.
      • Kullberg B.J.
      • Tack C.J.
      • van Krieken H.
      • Kim S.H.
      • Stalenhoef A.F.
      • van de Loo F.A.
      • Verschueren I.
      • Pulawa L.
      • Akira S.
      • Eckel R.H.
      • Dinarello C.A.
      • van den Berg W.
      • van der Meer J.W.
      Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.
      IL-1αLower fasting glucose and insulin with improved insulin sensitivity
      • Matsuki T.
      • Horai R.
      • Sudo K.
      • Iwakura Y.
      IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions.
      ResistinImproved glucose tolerance on HFD
      • Banerjee R.R.
      • Rangwala S.M.
      • Shapiro J.S.
      • Rich A.S.
      • Rhoades B.
      • Qi Y.
      • Wang J.
      • Rajala M.W.
      • Pocai A.
      • Scherer P.E.
      • Steppan C.M.
      • Ahima R.S.
      • Obici S.
      • Rossetti L.
      • Lazar M.A.
      Regulation of fasted blood glucose by resistin.
      MCP-1Decreased monocyte recruitment to adipose tissue, decreased adiposity, hepatic steatosis, and insulin resistance
      • Kanda H.
      • Tateya S.
      • Tamori Y.
      • Kotani K.
      • Hiasa K.
      • Kitazawa R.
      • Kitazawa S.
      • Miyachi H.
      • Maeda S.
      • Egashira K.
      • Kasuga M.
      MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
      • Weisberg S.P.
      • Hunter D.
      • Huber R.
      • Lemieux J.
      • Slaymaker S.
      • Vaddi K.
      • Charo I.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
      ICAM-1Exacerbation of obesity and increased susceptibility to diet-induced insulin resistance
      • Dong Z.M.
      • Gutierrez-Ramos J.C.
      • Coxon A.
      • Mayadas T.N.
      • Wagner D.D.
      A new class of obesity genes encodes leukocyte adhesion receptors.
      iNOSProtection against HFD-induced insulin resistance
      • Perreault M.
      • Marette A.
      Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.
      IKKβImproved insulin sensitivity
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • Melendez P.A.
      • Hansen L.
      • Lee J.
      • Shoelson S.E.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.
      • Arkan M.C.
      • Hevener A.L.
      • Greten F.R.
      • Maeda S.
      • Li Z.W.
      • Long J.M.
      • Wynshaw-Boris A.
      • Poli G.
      • Olefsky J.
      • Karin M.
      IKK-β links inflammation to obesity-induced insulin resistance.
      JNK1Improvement of insulin resistance in diet-induced and genetic obesity
      • Hirosumi J.
      • Tuncman G.
      • Chang L.
      • Gorgun C.Z.
      • Uysal K.T.
      • Maeda K.
      • Karin M.
      • Hotamisligil G.S.
      A central role for JNK in obesity and insulin resistance.
      SOCS1Decreased blood glucose levels and sustained insulin receptor phosphorylation
      • Kawazoe Y.
      • Naka T.
      • Fujimoto M.
      • Kohzaki H.
      • Morita Y.
      • Narazaki M.
      • Okumura K.
      • Saitoh H.
      • Nakagawa R.
      • Uchiyama Y.
      • Akira S.
      • Kishimoto T.
      Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation.
      ICAM, intracellular adhesion molecule; iNOS, inducible nitric oxide synthase; SOCS, suppressors of cytokine signaling.
      The effects of obesity-induced activation of NF-κB are primarily transcriptional and mediated through the synthesis of NF-κB target gene products.
      • Shoelson S.E.
      • Lee J.
      • Goldfine A.B.
      Inflammation and insulin resistance.
      By contrast, the effects of JNK are thought to be through the serine phosphorylation of the insulin receptor substrate (IRS)-1, which inhibits normal tyrosine phosphorylation of IRS-1 and downstream insulin signal transduction.
      • Hirosumi J.
      • Tuncman G.
      • Chang L.
      • Gorgun C.Z.
      • Uysal K.T.
      • Maeda K.
      • Karin M.
      • Hotamisligil G.S.
      A central role for JNK in obesity and insulin resistance.
      • Aguirre V.
      • Uchida T.
      • Yenush L.
      • Davis R.
      • White M.F.
      The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).
      • Aguirre V.
      • Werner E.D.
      • Giraud J.
      • Lee Y.H.
      • Shoelson S.E.
      • White M.F.
      Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action.
      • Werner E.D.
      • Lee J.
      • Hansen L.
      • Yuan M.
      • Shoelson S.E.
      Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302.
      In vivo, IKKβ does not directly impinge on insulin action, although it has been suggested that this could occur in cultured cells.
      • Gao Z.
      • Hwang D.
      • Bataille F.
      • Lefevre M.
      • York D.
      • Quon M.J.
      • Ye J.
      Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex.
      We have reviewed several of the gene products of NF-κB that act as potential mediators of obesity-induced pathology in the following section.

      NF-κB Target Gene Products: Potential Mediators of Insulin Resistance

       IL-6

      The proinflammatory cytokine IL-6 was among the first to be implicated as a predictor or pathogenic mediator of insulin resistance and CVD. There are increased circulating levels of IL-6 in patients with T2D.
      • Muller S.
      • Martin S.
      • Koenig W.
      • Hanifi-Moghaddam P.
      • Rathmann W.
      • Haastert B.
      • Giani G.
      • Illig T.
      • Thorand B.
      • Kolb H.
      Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors.
      • Pickup J.C.
      • Mattock M.B.
      • Chusney G.D.
      • Burt D.
      NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.
      A human polymorphism in the Il6 gene, which causes a decrease in circulating IL-6 levels, is associated with increased insulin sensitivity.
      • Fernandez-Real J.M.
      • Broch M.
      • Vendrell J.
      • Gutierrez C.
      • Casamitjana R.
      • Pugeat M.
      • Richart C.
      • Ricart W.
      Interleukin-6 gene polymorphism and insulin sensitivity.
      Concentrations of IL-6 decrease in parallel with weight loss and improvement of insulin resistance in patients undergoing bariatric surgery (Table 2).
      • Kopp H.P.
      • Kopp C.W.
      • Festa A.
      • Krzyzanowska K.
      • Kriwanek S.
      • Minar E.
      • Roka R.
      • Schernthaner G.
      Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.
      IL-6 production in abdominal adipose tissue is 3-fold higher compared with subcutaneous adipose tissue, indicating that IL-6 might be one of the factors that makes abdominal adipose tissue a high risk factor for the development of insulin resistance.
      • Fried S.K.
      • Bunkin D.A.
      • Greenberg A.S.
      Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
      IL-6 may also have an important role in hepatic insulin resistance. Insulin sensitivity increases in diet-induced obese mice treated with IL-6 antibodies, which appears to be due to amelioration of hepatic insulin resistance.
      • Klover P.J.
      • Clementi A.H.
      • Mooney R.A.
      Interleukin-6 depletion selectively improves hepatic insulin action in obesity.
      Chronic treatment with IL-6 also inhibits autophosphorylation of insulin receptor and downstream signaling mediators in liver.
      • Klover P.J.
      • Zimmers T.A.
      • Koniaris L.G.
      • Mooney R.A.
      Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice.
      Decreased hepatic and skeletal muscle insulin action that accompany treatment with IL-6 may be reversed by cotreatment with the anti-inflammatory cytokine IL-10.
      • Kim H.J.
      • Higashimori T.
      • Park S.Y.
      • Choi H.
      • Dong J.
      • Kim Y.J.
      • Noh H.L.
      • Cho Y.R.
      • Cline G.
      • Kim Y.B.
      • Kim J.K.
      Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
      IL-6-deficient mice, however, are insulin resistant and diabetic (Table 1),
      • Wallenius V.
      • Wallenius K.
      • Ahren B.
      • Rudling M.
      • Carlsten H.
      • Dickson S.L.
      • Ohlsson C.
      • Jansson J.O.
      Interleukin-6-deficient mice develop mature-onset obesity.
      which in itself would not be consistent with IL-6 as a mediator of insulin resistance but might be due to developmental or other unknown effects of loss of IL-6.
      Table 2Changes in Inflammatory Factors After Interventions for Insulin Resistance in Humans
      InterventionFactors changed
      Weight loss, diet, and exerciseDecrease in serum CRP,
      • Kopp H.P.
      • Kopp C.W.
      • Festa A.
      • Krzyzanowska K.
      • Kriwanek S.
      • Minar E.
      • Roka R.
      • Schernthaner G.
      Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.
      • McLaughlin T.
      • Abbasi F.
      • Lamendola C.
      • Liang L.
      • Reaven G.
      • Schaaf P.
      • Reaven P.
      Differentiation between obesity and insulin resistance in the association with C-reactive protein.
      • Ryan A.S.
      • Nicklas B.J.
      Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women.
      IL-6,
      • Ryan A.S.
      • Nicklas B.J.
      Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women.
      and SAA
      • Yang R.Z.
      • Lee M.J.
      • Hu H.
      • Pollin T.I.
      • Ryan A.S.
      • Nicklas B.J.
      • Snitker S.
      • Horenstein R.B.
      • Hull K.
      • Goldberg N.H.
      • Goldberg A.P.
      • Shuldiner A.R.
      • Fried S.K.
      • Gong D.W.
      Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
      after weight lost in postmenopausal women
      Decrease in serum CRP, MMP9, VCAM-1, and P-selectin after high-fiber, low-fat diet and exercise
      • Roberts C.K.
      • Won D.
      • Pruthi S.
      • Kurtovic S.
      • Sindhu R.K.
      • Vaziri N.D.
      • Barnard R.J.
      Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors.
      Decrease in serum CRP after intensive physical training
      • Oberbach A.
      • Tonjes A.
      • Kloting N.
      • Fasshauer M.
      • Kratzsch J.
      • Busse M.W.
      • Paschke R.
      • Stumvoll M.
      • Bluher M.
      Effect of a 4-week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance.
      Bariatic surgeryDecrease in serum IL-6,
      • Kopp H.P.
      • Kopp C.W.
      • Festa A.
      • Krzyzanowska K.
      • Kriwanek S.
      • Minar E.
      • Roka R.
      • Schernthaner G.
      Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.
      PAI-1,
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      • Primrose J.N.
      • Davies J.A.
      • Prentice C.R.
      • Hughes R.
      • Johnston D.
      Reduction in factor VII, fibrinogen and plasminogen activator inhibitor-1 activity after surgical treatment of morbid obesity.
      E-selectin,
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      P-selectin,
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      TNF-αR2,
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      CRP,
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      • Schernthaner G.H.
      • Kopp H.P.
      • Krzyzanowska K.
      • Kriwanek S.
      • Koppensteiner R.
      • Schernthaner G.
      Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
      • Kopp H.P.
      • Krzyzanowska K.
      • Mohlig M.
      • Spranger J.
      • Pfeiffer A.F.
      • Schernthaner G.
      Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women.
      CD40L,
      • Schernthaner G.H.
      • Kopp H.P.
      • Krzyzanowska K.
      • Kriwanek S.
      • Koppensteiner R.
      • Schernthaner G.
      Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
      MCP-1,
      • Schernthaner G.H.
      • Kopp H.P.
      • Krzyzanowska K.
      • Kriwanek S.
      • Koppensteiner R.
      • Schernthaner G.
      Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
      and adiponectin
      • Kopp H.P.
      • Krzyzanowska K.
      • Mohlig M.
      • Spranger J.
      • Pfeiffer A.F.
      • Schernthaner G.
      Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women.
      ThiazolidinedionesDecrease in serum MMP9,
      • Haffner S.M.
      • Greenberg A.S.
      • Weston W.M.
      • Chen H.
      • Williams K.
      • Freed M.I.
      Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus.
      CRP,
      • Haffner S.M.
      • Greenberg A.S.
      • Weston W.M.
      • Chen H.
      • Williams K.
      • Freed M.I.
      Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus.
      PAI-1,
      • Chu J.W.
      • Abbasi F.
      • Lamendola C.
      • McLaughlin T.
      • Reaven G.M.
      • Tsao P.S.
      Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects.
      MCP-1,
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      CRP,
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      • Hung Y.J.
      • Lin S.H.
      • Pei D.
      • Kuo S.W.
      • Hsieh C.H.
      • He C.T.
      • Hsing Lee C.
      • Fan S.C.
      • Sheu W.H.
      Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein.
      resistin,
      • Jung H.S.
      • Youn B.S.
      • Cho Y.M.
      • Yu K.Y.
      • Park H.J.
      • Shin C.S.
      • Kim S.Y.
      • Lee H.K.
      • Park K.S.
      The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus.
      and SAA
      • Yang R.Z.
      • Lee M.J.
      • Hu H.
      • Pollin T.I.
      • Ryan A.S.
      • Nicklas B.J.
      • Snitker S.
      • Horenstein R.B.
      • Hull K.
      • Goldberg N.H.
      • Goldberg A.P.
      • Shuldiner A.R.
      • Fried S.K.
      • Gong D.W.
      Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
      after rosiglitazone treatment
      Decrease in serum CRP after troglitazone treatment
      • Chu N.V.
      • Kong A.P.
      • Kim D.D.
      • Armstrong D.
      • Baxi S.
      • Deutsch R.
      • Caulfield M.
      • Mudaliar S.R.
      • Reitz R.
      • Henry R.R.
      • Reaven P.D.
      Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.
      Decrease in serum TNF-α
      • Di Gregorio G.B.
      • Yao-Borengasser A.
      • Rasouli N.
      • Varma V.
      • Lu T.
      • Miles L.M.
      • Ranganathan G.
      • Peterson C.A.
      • McGehee R.E.
      • Kern P.A.
      Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.
      and resistin
      • Bajaj M.
      • Suraamornkul S.
      • Hardies L.J.
      • Pratipanawatr T.
      • DeFronzo R.A.
      Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients.
      after pioglitazone treatment
      • Di Gregorio G.B.
      • Yao-Borengasser A.
      • Rasouli N.
      • Varma V.
      • Lu T.
      • Miles L.M.
      • Ranganathan G.
      • Peterson C.A.
      • McGehee R.E.
      • Kern P.A.
      Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.
      MetforminDecrease in serum CRP
      • Chu N.V.
      • Kong A.P.
      • Kim D.D.
      • Armstrong D.
      • Baxi S.
      • Deutsch R.
      • Caulfield M.
      • Mudaliar S.R.
      • Reitz R.
      • Henry R.R.
      • Reaven P.D.
      Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.
      • Akbar D.H.
      Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome.
      SulfonylureasDecrease in serum IL-6
      • Drzewoski J.
      • Zurawska-Klis M.
      Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-α plasma levels in individuals with type 2 diabetes mellitus.
      and E-selectin
      • Desfaits A.C.
      • Serri O.
      • Renier G.
      Normalization of plasma lipid peroxides, monocyte adhesion, and tumor necrosis factor-α production in NIDDM patients after gliclazide treatment.
      and increase in adiponectin
      • Drzewoski J.
      • Zurawska-Klis M.
      Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-α plasma levels in individuals with type 2 diabetes mellitus.
      with gliclazide treatment
      MMP, matrix metalloproteinase; VCAM-1, vascular-cell adhesion molecule 1.

       IL-10

      IL-10 is an anti-inflammatory cytokine whose decreased production has been associated with the development of T2D and whose plasma levels may positively correlate with insulin sensitivity.
      • van Exel E.
      • Gussekloo J.
      • de Craen A.J.
      • Frolich M.
      • Bootsma-Van Der Wiel A.
      • Westendorp R.G.
      Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-plus study.
      • Straczkowski M.
      • Kowalska I.
      • Nikolajuk A.
      • Krukowska A.
      • Gorska M.
      Plasma interleukin-10 concentration is positively related to insulin sensitivity in young healthy individuals.
      Lower IL-10 levels have been associated with the metabolic syndrome in obese insulin resistant postmenopausal women compared with women who are obese and do not fulfil criteria for having the syndrome.
      • Esposito K.
      • Pontillo A.
      • Di Palo C.
      • Giugliano G.
      • Masella M.
      • Marfella R.
      • Giugliano D.
      Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.
      As noted above, IL-10 decreases IL-6-induced insulin resistance in muscle and liver in mice cotreated with IL-6 and IL-10.
      • Kim H.J.
      • Higashimori T.
      • Park S.Y.
      • Choi H.
      • Dong J.
      • Kim Y.J.
      • Noh H.L.
      • Cho Y.R.
      • Cline G.
      • Kim Y.B.
      • Kim J.K.
      Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
      A recent study showed that IL-10 is expressed in macrophages derived from adipose tissue and that the IL-10 receptor is expressed in adipocytes and not immune or endothelial cells in fat.
      • Lumeng C.N.
      • Bodzin J.L.
      • Saltiel A.R.
      Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
      IL-10 treatment of cultured 3T3-L1 adipocytes decreased MCP-1 secretion and reversed the decreases in GLUT4 levels and IRS-1 tyrosine phosphorylation that were induced by TNF-α treatment. These studies indicate that IL-10 is an antiinflammatory factor produced by immune cells in adipose tissue that acts on adipocytes to improve insulin signaling, potentially decreasing further macrophage recruitment.

       TNF-α

      TNF-α is a cytokine secreted both by immune cells and adipocytes. In adipose tissue, it has been thought to play a role in the development of insulin resistance.
      • Hotamisligil G.S.
      • Shargill N.S.
      • Spiegelman B.M.
      Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.
      TNF-α mRNA levels in adipose tissue of ob/ob mice are significantly increased compared with wild-type (WT) controls.
      • Schafer K.
      • Fujisawa K.
      • Konstantinides S.
      • Loskutoff D.J.
      Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice.
      mRNA and protein levels of TNF-α have also been shown to be increased in adipose tissue of obese individuals compared with lean human subjects, and this has been positively correlated with plasma insulin levels.
      • Hotamisligil G.S.
      • Arner P.
      • Caro J.F.
      • Atkinson R.L.
      • Spiegelman B.M.
      Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance.
      Additional studies have reported increases in serum TNF-α in human subjects with insulin resistance,
      • Dandona P.
      • Weinstock R.
      • Thusu K.
      • Abdel-Rahman E.
      • Aljada A.
      • Wadden T.
      Tumor necrosis factor-α in sera of obese patients: fall with weight loss.
      • Katsuki A.
      • Sumida Y.
      • Murashima S.
      • Murata K.
      • Takarada Y.
      • Ito K.
      • Fujii M.
      • Tsuchihashi K.
      • Goto H.
      • Nakatani K.
      • Yano Y.
      Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent diabetes mellitus.
      although others have reported the converse.
      • Muller S.
      • Martin S.
      • Koenig W.
      • Hanifi-Moghaddam P.
      • Rathmann W.
      • Haastert B.
      • Giani G.
      • Illig T.
      • Thorand B.
      • Kolb H.
      Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors.
      • Bruun J.M.
      • Verdich C.
      • Toubro S.
      • Astrup A.
      • Richelsen B.
      Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-α Effect of weight loss in obese men.
      Importantly, studies using neutralizing anti-TNF-α antibodies in humans did not show improved insulin sensitivity.
      • Bernstein L.E.
      • Berry J.
      • Kim S.
      • Canavan B.
      • Grinspoon S.K.
      Effects of etanercept in patients with the metabolic syndrome.
      • Ofei F.
      • Hurel S.
      • Newkirk J.
      • Sopwith M.
      • Taylor R.
      Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
      Levels of TNF-α may change with thiazolidinedione (TZD) treatment, although conflicting results have been reported.
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      • Di Gregorio G.B.
      • Yao-Borengasser A.
      • Rasouli N.
      • Varma V.
      • Lu T.
      • Miles L.M.
      • Ranganathan G.
      • Peterson C.A.
      • McGehee R.E.
      • Kern P.A.
      Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.
      Although TNF-α knockout mice are reported to be protected against diet-induced insulin resistance,
      • Uysal K.T.
      • Wiesbrock S.M.
      • Marino M.W.
      • Hotamisligil G.S.
      Protection from obesity-induced insulin resistance in mice lacking TNF-α function.
      the effects of deleting the TNF-α receptors p55 and p75 are more complex and have been shown to either improve or exacerbate insulin resistance.
      • Uysal K.T.
      • Wiesbrock S.M.
      • Marino M.W.
      • Hotamisligil G.S.
      Protection from obesity-induced insulin resistance in mice lacking TNF-α function.
      • Schreyer S.A.
      • Chua Jr, S.C.
      • LeBoeuf R.C.
      Obesity and diabetes in TNF-α receptor- deficient mice.
      Bariatric surgery decreases the circulating levels of TNF-αR2 (Table 2).
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.

       IL-1α and IL-1β

      IL-1α and IL-1β are proinflammatory cytokines that exert similar but not redundant functions through engagement of IL-1 receptors. Il1α−/ mice have lower fasting glucose and insulin levels and improved insulin sensitivity as determined by insulin tolerance testing, compared with WT controls.
      • Matsuki T.
      • Horai R.
      • Sudo K.
      • Iwakura Y.
      IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions.
      mRNA expression of IL-lβ was increased in the epididymal fat pads of insulin resistant HFD-fed mice and ob/ob mice compared with low-fat-fed mice and WT mice, respectively.
      • Lagathu C.
      • Yvan-Charvet L.
      • Bastard J.P.
      • Maachi M.
      • Quignard-Boulange A.
      • Capeau J.
      • Caron M.
      Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes.
      Circulating IL-1β levels are increased in the insulin resistant fatless A-ZIP/F-1 transgenic mouse.
      • Nunez N.P.
      • Oh W.J.
      • Rozenberg J.
      • Perella C.
      • Anver M.
      • Barrett J.C.
      • Perkins S.N.
      • Berrigan D.
      • Moitra J.
      • Varticovski L.
      • Hursting S.D.
      • Vinson C.
      Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation.
      IL-1β together with IL-6 concentrations reportedly predicts risk for T2D in humans better than either cytokine alone.
      • Spranger J.
      • Kroke A.
      • Mohlig M.
      • Hoffmann K.
      • Bergmann M.M.
      • Ristow M.
      • Boeing H.
      • Pfeiffer A.F.
      Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.

       Resistin

      Resistin is an inflammatory cytokine produced in adipocytes and immune cells whose expression is suppressed by TZDs (Table 2) and up-regulated by proinflammatory cytokines and bacterially derived lipopolysaccharide.
      • Steppan C.M.
      • Bailey S.T.
      • Bhat S.
      • Brown E.J.
      • Banerjee R.R.
      • Wright C.M.
      • Patel H.R.
      • Ahima R.S.
      • Lazar M.A.
      The hormone resistin links obesity to diabetes.
      • Bajaj M.
      • Suraamornkul S.
      • Hardies L.J.
      • Pratipanawatr T.
      • DeFronzo R.A.
      Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients.
      • Kaser S.
      • Kaser A.
      • Sandhofer A.
      • Ebenbichler C.F.
      • Tilg H.
      • Patsch J.R.
      Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro.
      Although resistin was first identified in mouse adipose tissue as a negatively regulated peroxisome proliferator-activated receptor γ (PPARγ) responsive gene, its expression profile in humans is prominent in immune cells including macrophages. In addition, the protein sequences of resistin in man and mouse are only 55% identical, suggesting that resistin may in some cases serve certain distinct, nonconserved functions in different species. Like many other proinflammatory cytokines, resistin stimulates intracellular signaling through NF-κB activation, which in turn promotes the synthesis of other proinflammatory cytokines, including TNF-α, IL-6, MCP-1, and IL-12, and the surface adhesion molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1.
      • Kaser S.
      • Kaser A.
      • Sandhofer A.
      • Ebenbichler C.F.
      • Tilg H.
      • Patsch J.R.
      Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro.
      • Bokarewa M.
      • Nagaev I.
      • Dahlberg L.
      • Smith U.
      • Tarkowski A.
      Resistin, an adipokine with potent proinflammatory properties.
      • Silswal N.
      • Singh A.K.
      • Aruna B.
      • Mukhopadhyay S.
      • Ghosh S.
      • Ehtesham N.Z.
      Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-κB-dependent pathway.
      • Verma S.
      • Li S.H.
      • Wang C.H.
      • Fedak P.W.
      • Li R.K.
      • Weisel R.D.
      • Mickle D.A.
      Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction.
      Consistent with the feed forward, “positive feedback loop” nature of NF-κB-mediated inflammatory signaling, various proinflammatory stimuli also induce the expression of resistin, including TNF-α, IL-6, IL-1β, and lipopolysaccharide.
      • Kaser S.
      • Kaser A.
      • Sandhofer A.
      • Ebenbichler C.F.
      • Tilg H.
      • Patsch J.R.
      Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro.
      In addition to its potential roles in insulin resistance, resistin may play a role in the inflammation associated with the pathogenesis of CVD.
      • Reilly M.P.
      • Lehrke M.
      • Wolfe M.L.
      • Rohatgi A.
      • Lazar M.A.
      • Rader D.J.
      Resistin is an inflammatory marker of atherosclerosis in humans.

       MCP-1

      MCP-1 (also called CCL2) is a chemoattractive protein that recruits immune cells to sites of inflammation. The adipose tissue expression of MCP-1 increases in proportion to adiposity and decreases following treatment with TZDs
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      • Di Gregorio G.B.
      • Yao-Borengasser A.
      • Rasouli N.
      • Varma V.
      • Lu T.
      • Miles L.M.
      • Ranganathan G.
      • Peterson C.A.
      • McGehee R.E.
      • Kern P.A.
      Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.
      and following bariatic surgery (Table 2).
      • Schernthaner G.H.
      • Kopp H.P.
      • Krzyzanowska K.
      • Kriwanek S.
      • Koppensteiner R.
      • Schernthaner G.
      Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
      MCP-1 gene expression in adipose tissue is increased in diet-induced insulin resistance and in ob/ob and db/db mice.
      • Kanda H.
      • Tateya S.
      • Tamori Y.
      • Kotani K.
      • Hiasa K.
      • Kitazawa R.
      • Kitazawa S.
      • Miyachi H.
      • Maeda S.
      • Egashira K.
      • Kasuga M.
      MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
      • Kamei N.
      • Tobe K.
      • Suzuki R.
      • Ohsugi M.
      • Watanabe T.
      • Kubota N.
      • Ohtsuka-Kowatari N.
      • Kumagai K.
      • Sakamoto K.
      • Kobayashi M.
      • Yamauchi T.
      • Ueki K.
      • Oishi Y.
      • Nishimura S.
      • Manabe I.
      • Hashimoto H.
      • Ohnishi Y.
      • Ogata H.
      • Tokuyama K.
      • Tsunoda M.
      • Ide T.
      • Murakami K.
      • Nagai R.
      • Kadowaki T.
      Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.
      Two independent studies convincingly showed that the adipocyte-specific overexpression of MCP-1 in mice was sufficient to increase macrophage recruitment to adipose tissue and cause systemic insulin resistance; notably, MCP-1 expression in adipocytes resulted in hepatic steatosis and insulin resistance in liver and muscle as well as in fat.
      • Kanda H.
      • Tateya S.
      • Tamori Y.
      • Kotani K.
      • Hiasa K.
      • Kitazawa R.
      • Kitazawa S.
      • Miyachi H.
      • Maeda S.
      • Egashira K.
      • Kasuga M.
      MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
      • Kamei N.
      • Tobe K.
      • Suzuki R.
      • Ohsugi M.
      • Watanabe T.
      • Kubota N.
      • Ohtsuka-Kowatari N.
      • Kumagai K.
      • Sakamoto K.
      • Kobayashi M.
      • Yamauchi T.
      • Ueki K.
      • Oishi Y.
      • Nishimura S.
      • Manabe I.
      • Hashimoto H.
      • Ohnishi Y.
      • Ogata H.
      • Tokuyama K.
      • Tsunoda M.
      • Ide T.
      • Murakami K.
      • Nagai R.
      • Kadowaki T.
      Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.
      Concordantly, mice deficient in CCR2, a major cell surface receptor for MCP-1, have fewer monocytes recruited to fat and are protected against the development of obesity-induced insulin resistance (Table 1).
      • Weisberg S.P.
      • Hunter D.
      • Huber R.
      • Lemieux J.
      • Slaymaker S.
      • Vaddi K.
      • Charo I.
      • Leibel R.L.
      • Ferrante Jr, A.W.
      CCR2 modulates inflammatory and metabolic effects of high-fat feeding.

       CRP

      CRP is an acute phase reactant produced mainly in the liver in response to IL-6. The circulating concentrations of CRP are considered to be a marker for cardiovascular risk and have also been correlated with insulin resistance.
      • Muller S.
      • Martin S.
      • Koenig W.
      • Hanifi-Moghaddam P.
      • Rathmann W.
      • Haastert B.
      • Giani G.
      • Illig T.
      • Thorand B.
      • Kolb H.
      Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors.
      • Festa A.
      • Williams K.
      • Tracy R.P.
      • Wagenknecht L.E.
      • Haffner S.M.
      Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type 2 diabetes.
      • Leinonen E.
      • Hurt-Camejo E.
      • Wiklund O.
      • Hulten L.M.
      • Hiukka A.
      • Taskinen M.R.
      Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes.
      • Pannacciulli N.
      • Cantatore F.P.
      • Minenna A.
      • Bellacicco M.
      • Giorgino R.
      • De Pergola G.
      C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women.
      CRP levels are higher in obese subjects who are also insulin resistant and decrease with weight loss and improvement of insulin sensitivity.
      • Kopp H.P.
      • Kopp C.W.
      • Festa A.
      • Krzyzanowska K.
      • Kriwanek S.
      • Minar E.
      • Roka R.
      • Schernthaner G.
      Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.
      • McLaughlin T.
      • Abbasi F.
      • Lamendola C.
      • Liang L.
      • Reaven G.
      • Schaaf P.
      • Reaven P.
      Differentiation between obesity and insulin resistance in the association with C-reactive protein.
      Circulating levels of CRP may decrease following bariatic surgery
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      • Schernthaner G.H.
      • Kopp H.P.
      • Krzyzanowska K.
      • Kriwanek S.
      • Koppensteiner R.
      • Schernthaner G.
      Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
      • Kopp H.P.
      • Krzyzanowska K.
      • Mohlig M.
      • Spranger J.
      • Pfeiffer A.F.
      • Schernthaner G.
      Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women.
      and during treatment with TZDs (Table 2).
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      • Chu N.V.
      • Kong A.P.
      • Kim D.D.
      • Armstrong D.
      • Baxi S.
      • Deutsch R.
      • Caulfield M.
      • Mudaliar S.R.
      • Reitz R.
      • Henry R.R.
      • Reaven P.D.
      Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.
      • Hung Y.J.
      • Lin S.H.
      • Pei D.
      • Kuo S.W.
      • Hsieh C.H.
      • He C.T.
      • Hsing Lee C.
      • Fan S.C.
      • Sheu W.H.
      Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein.
      A debate continues on whether CRP is a marker vs a potential pathophysiologic mediator in CVD and insulin resistance.

       SAA

      The SAA proteins are derived from distinct genes; humans express SAA1, SAA2, and SAA4. Because SAA1 and SAA2 expression increases dramatically during acute inflammatory responses, these are referred to as acute phase SAA. Although SAA1 and SAA2 are produced mostly in liver in other animals, recent studies suggest that, in humans, adipocytes may be a major contributor.
      • Yang R.Z.
      • Lee M.J.
      • Hu H.
      • Pollin T.I.
      • Ryan A.S.
      • Nicklas B.J.
      • Snitker S.
      • Horenstein R.B.
      • Hull K.
      • Goldberg N.H.
      • Goldberg A.P.
      • Shuldiner A.R.
      • Fried S.K.
      • Gong D.W.
      Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
      Moreover, large adipocytes, which have been associated with increased insulin resistance, have higher mRNA expression of SAA2 than smaller adipocytes.
      • Jernas M.
      • Palming J.
      • Sjoholm K.
      • Jennische E.
      • Svensson P.A.
      • Gabrielsson B.G.
      • Levin M.
      • Sjogren A.
      • Rudemo M.
      • Lystig T.C.
      • Carlsson B.
      • Carlsson L.M.
      • Lonn M.
      Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression.
      Circulating SAA levels are increased in individuals with impaired glucose tolerance and T2D
      • Muller S.
      • Martin S.
      • Koenig W.
      • Hanifi-Moghaddam P.
      • Rathmann W.
      • Haastert B.
      • Giani G.
      • Illig T.
      • Thorand B.
      • Kolb H.
      Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors.
      and decrease in obese subjects upon weight loss or treatment with TZDs (Table 2).
      • Yang R.Z.
      • Lee M.J.
      • Hu H.
      • Pollin T.I.
      • Ryan A.S.
      • Nicklas B.J.
      • Snitker S.
      • Horenstein R.B.
      • Hull K.
      • Goldberg N.H.
      • Goldberg A.P.
      • Shuldiner A.R.
      • Fried S.K.
      • Gong D.W.
      Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
      In cultured cells, SAA induces the expression of several other potential inflammatory markers and mediators, including IL-6, IL-8, MCP-1, and PAI-1, suggesting that it might have related functions in vivo.
      • Yang R.Z.
      • Lee M.J.
      • Hu H.
      • Pollin T.I.
      • Ryan A.S.
      • Nicklas B.J.
      • Snitker S.
      • Horenstein R.B.
      • Hull K.
      • Goldberg N.H.
      • Goldberg A.P.
      • Shuldiner A.R.
      • Fried S.K.
      • Gong D.W.
      Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.

       IL-8

      IL-8 is the prototypical CXC chemokine and is known to recruit and activate monocytes and to attract polymorphonuclear leukocytes to sites of inflammation. IL-8 levels have been reported to be increased in obese insulin resistant males but did not decrease with improvement of insulin sensitivity and weight loss.
      • Bruun J.M.
      • Verdich C.
      • Toubro S.
      • Astrup A.
      • Richelsen B.
      Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-α Effect of weight loss in obese men.

       PAI-1

      PAI-1 inhibits plasminogen activators, which convert inactive plasminogen into plasmin during fibrinolysis. PAI-1 is considered to be a cardiovascular risk factor, although PAI-1 concentrations also correlate with peripheral insulin resistance in obese type 2 diabetic patients.
      • Festa A.
      • Williams K.
      • Tracy R.P.
      • Wagenknecht L.E.
      • Haffner S.M.
      Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type 2 diabetes.
      • Potter van Loon B.J.
      • Kluft C.
      • Radder J.K.
      • Blankenstein M.A.
      • Meinders A.E.
      The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance.
      WT mice fed an HFD developed hyperglycemia and hyperinsulinemia and have approximately 2.5-fold increases in PAI-1 mRNA expression in adipose tissue and plasma PAI-1 levels, compared with chow-fed control mice.
      • Ma L.J.
      • Mao S.L.
      • Taylor K.L.
      • Kanjanabuch T.
      • Guan Y.
      • Zhang Y.
      • Brown N.J.
      • Swift L.L.
      • McGuinness O.P.
      • Wasserman D.H.
      • Vaughan D.E.
      • Fogo A.B.
      Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
      Deletion of PAI-1 in knockout mice renders them more insulin sensitive on HFD compared with WT mice on the same diet.
      • Ma L.J.
      • Mao S.L.
      • Taylor K.L.
      • Kanjanabuch T.
      • Guan Y.
      • Zhang Y.
      • Brown N.J.
      • Swift L.L.
      • McGuinness O.P.
      • Wasserman D.H.
      • Vaughan D.E.
      • Fogo A.B.
      Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
      Pai1−/ mice on an ob/ob background are also more insulin sensitive and have lower circulating TNF-α levels than their Pai1+/+ ob/ob counterparts.
      • Schafer K.
      • Fujisawa K.
      • Konstantinides S.
      • Loskutoff D.J.
      Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice.
      TZD treatment
      • Chu J.W.
      • Abbasi F.
      • Lamendola C.
      • McLaughlin T.
      • Reaven G.M.
      • Tsao P.S.
      Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects.
      and bariatric surgery
      • Vazquez L.A.
      • Pazos F.
      • Berrazueta J.R.
      • Fernandez-Escalante C.
      • Garcia-Unzueta M.T.
      • Freijanes J.
      • Amado J.A.
      Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
      • Primrose J.N.
      • Davies J.A.
      • Prentice C.R.
      • Hughes R.
      • Johnston D.
      Reduction in factor VII, fibrinogen and plasminogen activator inhibitor-1 activity after surgical treatment of morbid obesity.
      both decrease circulating levels of PAI-1 in parallel with their effects on insulin resistance (Table 1, Table 2).

      Drugs That Either Target or Reduce Inflammation as Potential Treatments for Insulin Resistance

      The hypothesis that TNF-α is involved in the pathogenesis of insulin resistance and the availability of biologic TNF-α blocking reagents provided both rationale and means for the testing of pharmacologically-directed anti-inflammatory therapies. In support of this approach, the infusion of a TNF receptor IgG fusion protein was found to improve insulin sensitivity in mice.
      • Hotamisligil G.S.
      • Shargill N.S.
      • Spiegelman B.M.
      Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.
      Because TNF-α targeted biologic reagents are in clinical use for treating patients with various inflammatory conditions including rheumatoid arthritis, the reagents are available for asking whether the blocking of TNF-α might also improve insulin resistance. However, the results have not been promising. Single doses of TNF-α receptor antagonists failed to improve insulin resistance in diabetic or obese subjects.
      • Ofei F.
      • Hurel S.
      • Newkirk J.
      • Sopwith M.
      • Taylor R.
      Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
      • Paquot N.
      • Castillo M.J.
      • Lefebvre P.J.
      • Scheen A.J.
      No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients.
      Subsequent placebo-controlled trials, each conducted for 4 weeks duration, similarly provided no benefits in terms of improvements in insulin sensitivity. The first trial was conducted with obese, diabetic subjects,
      • Dominguez H.
      • Storgaard H.
      • Rask-Madsen C.
      • Steffen Hermann T.
      • Ihlemann N.
      • Baunbjerg Nielsen D.
      • Spohr C.
      • Kober L.
      • Vaag A.
      • Torp-Pedersen C.
      Metabolic and vascular effects of tumor necrosis factor-α blockade with etanercept in obese patients with type 2 diabetes.
      whereas the second was with obese, insulin resistant subjects without diabetes.
      • Bernstein L.E.
      • Berry J.
      • Kim S.
      • Canavan B.
      • Grinspoon S.K.
      Effects of etanercept in patients with the metabolic syndrome.
      Thus, TNF-α blockade appears to have limited utility in humans with insulin resistance, either as a potential treatment or even as a tool for discriminating potential pathophysiologic mechanisms.
      The insulin sensitizing TZDs have been shown to have anti-inflammatory activities in addition to their established role in regulating glucose homeostasis.
      • Mohanty P.
      • Aljada A.
      • Ghanim H.
      • Hofmeyer D.
      • Tripathy D.
      • Syed T.
      • Al-Haddad W.
      • Dhindsa S.
      • Dandona P.
      Evidence for a potent anti-inflammatory effect of rosiglitazone.
      • Jiang C.
      • Ting A.T.
      • Seed B.
      PPAR-γ agonists inhibit production of monocyte inflammatory cytokines.
      • Ricote M.
      • Li A.C.
      • Willson T.M.
      • Kelly C.J.
      • Glass C.K.
      The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation.
      • Aljada A.
      • Garg R.
      • Ghanim H.
      • Mohanty P.
      • Hamouda W.
      • Assian E.
      • Dandona P.
      Nuclear factor-κB suppressive and inhibitor-κB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an anti-inflammatory action?.
      • Ghanim H.
      • Garg R.
      • Aljada A.
      • Mohanty P.
      • Kumbkarni Y.
      • Assian E.
      • Hamouda W.
      • Dandona P.
      Suppression of nuclear factor-κB and stimulation of inhibitor κB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese.
      TZDs exert their effects by binding and activating the nuclear hormone receptor PPARγ. TZD binding induces the expression of several genes involved in adipocyte differentiation, lipid and glucose uptake, and fatty acid storage.
      • Yki-Jarvinen H.
      Thiazolidinediones.
      The beneficial effects of TZDs as insulin sensitizers are thought to be due primarily to the promotion of fatty acid storage into the adipose tissue, which decreases circulating FFA and redistributes lipids from other tissues such as muscle and liver into the adipose tissue. Because intracellular lipid in muscle and liver promotes insulin resistance, the redistribution of lipid out of these tissues is considered to be the major mechanism for the insulin sensitizing effects of the TZDs. Proposed mechanisms for the anti-inflammatory properties of TZDs include PPARγ-independent activation of the glucocorticoid receptor,
      • Ialenti A.
      • Grassia G.
      • Di Meglio P.
      • Maffia P.
      • Di Rosa M.
      • Ianaro A.
      Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway.
      although alternative explanations are gaining favor. The transrepression of subsets of NF-κB and JNK/activating protein-1 induced genes by TZD-bound PPARγ is a likely candidate.
      • Ricote M.
      • Li A.C.
      • Willson T.M.
      • Kelly C.J.
      • Glass C.K.
      The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation.
      • Pascual G.
      • Fong A.L.
      • Ogawa S.
      • Gamliel A.
      • Li A.C.
      • Perissi V.
      • Rose D.W.
      • Willson T.M.
      • Rosenfeld M.G.
      • Glass C.K.
      A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ.
      This is thought to occur through the ligand-induced addition of small ubiquitin-related modifier (SUMO) to PPARγ.
      • Pascual G.
      • Fong A.L.
      • Ogawa S.
      • Gamliel A.
      • Li A.C.
      • Perissi V.
      • Rose D.W.
      • Willson T.M.
      • Rosenfeld M.G.
      • Glass C.K.
      A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ.
      SUMOylated PPARγ is thought to stabilize corepressor complexes incorporating NF-κB and AP-1 bound to inflammatory gene promoters, thus maintaining them in a repressed state. These effects have only been seen in vitro in RAW cells, a cultured macrophage cell line. At this time, it is not known whether this occurs in vivo and, if so, in which of the cell types that express PPARγ, which includes adipocytes, hepatocytes, endothelial cells, macrophages, and other immune cells. It is noteworthy that TZDs may prove to be useful in the management of NAFLD because pioglitazone has been shown to reduce hepatic inflammation, although it is not yet clear whether the benefit was due to a redistribution of lipid out of the liver or a more direct anti-inflammatory effect.
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • Darland C.
      • Finch J.
      • Hardies J.
      • Balas B.
      • Gastaldelli A.
      • Tio F.
      • Pulcini J.
      • Berria R.
      • Ma J.Z.
      • Dwivedi S.
      • Havranek R.
      • Fincke C.
      • DeFronzo R.
      • Bannayan G.A.
      • Schenker S.
      • Cusi K.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      The statins have also been shown to have anti-inflammatory properties. These drugs lower circulating cholesterol levels by inhibiting cellular 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. The levels of circulating markers and potential mediators of inflammation are also reduced in subjects treated with statins.
      • Weitz-Schmidt G.
      Statins as anti-inflammatory agents.
      Because levels of CRP and several proinflammatory cytokines decrease, and these are products of NF-κB genes, it appears that the statins may have modest anti-NF-κB activity. The mechanism for this is unknown but may be related to the lowering of oxidized low-density lipoprotein, which can stimulate NF-κB in certain cell types. The small decrease in the risk of developing T2D that accompanies statin therapy may be attributable to its anti-inflammatory activity.
      • Freeman D.J.
      • Norrie J.
      • Sattar N.
      • Neely R.D.
      • Cobbe S.M.
      • Ford I.
      • Isles C.
      • Lorimer A.R.
      • Macfarlane P.W.
      • McKillop J.H.
      • Packard C.J.
      • Shepherd J.
      • Gaw A.
      Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
      The anti-inflammatory properties of the TZDs and statins thus appear to be “off-target” and distinct from their primary mechanisms of action, suggesting that a more directed approach to targeting inflammation might be more beneficial. This possibility is supported by the rediscovery of the potent glucose-lowering effects of the anti-inflammatory drug salicylate.
      • Shoelson S.E.
      • Lee J.
      • Goldfine A.B.
      Inflammation and insulin resistance.
      • Yuan M.
      • Konstantopoulos N.
      • Lee J.
      • Hansen L.
      • Li Z.W.
      • Karin M.
      • Shoelson S.E.
      Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.
      Salicylates had been found long ago to lower glucose in patients with diabetes,
      • Baron S.H.
      Salicylates as hypoglycemic agents.
      • Ebstein W.
      Zur therapie des diabetes mellitus, insbesondere über die Anwendung des salicylsauren natron bei demselben.
      • Reid J.
      • Macdougall A.I.
      • Andrews M.M.
      On the efficacy of salicylate in treating diabetes mellitus.
      • Williamson R.
      On the treatment of glycosuria and diabetes mellitus with sodium salicylate.
      although connections to the pathogenesis of insulin resistance and in particular to a potential role for inflammation were not considered until recently.
      • Shoelson S.E.
      • Lee J.
      • Goldfine A.B.
      Inflammation and insulin resistance.
      • Yuan M.
      • Konstantopoulos N.
      • Lee J.
      • Hansen L.
      • Li Z.W.
      • Karin M.
      • Shoelson S.E.
      Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.
      • Hundal R.S.
      • Petersen K.F.
      • Mayerson A.B.
      • Randhawa P.S.
      • Inzucchi S.
      • Shoelson S.E.
      • Shulman G.I.
      Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
      The anti-inflammatory effect of salicylates has been attributed to the inhibition of IKKβ and NF-κB,
      • Yin M.J.
      • Yamamoto Y.
      • Gaynor R.B.
      The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(κ)B kinase-β.
      • Kopp E.
      • Ghosh S.
      Inhibition of NF-κB by sodium salicylate and aspirin.
      • Pierce J.W.
      • Read M.A.
      • Ding H.
      • Luscinskas F.W.
      • Collins T.
      Salicylates inhibit IκB-α phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration.
      which has led to our speculation that glucose lowering and insulin sensitization might also be due to NF-κB inhibition. Larger clinical trials using salsalate, a dimeric form of salicylate, are currently testing these hypotheses.

      References

      1. World Health Organization. Fact sheet: obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed February 8, 2007.

        • Weisberg S.P.
        • McCann D.
        • Desai M.
        • Rosenbaum M.
        • Leibel R.L.
        • Ferrante Jr, A.W.
        Obesity is associated with macrophage accumulation in adipose tissue.
        J Clin Invest. 2003; 112: 1796-1808
        • Xu H.
        • Barnes G.T.
        • Yang Q.
        • Tan G.
        • Yang D.
        • Chou C.J.
        • Sole J.
        • Nichols A.
        • Ross J.S.
        • Tartaglia L.A.
        • Chen H.
        Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
        J Clin Invest. 2003; 112: 1821-1830
        • Krauss S.
        • Zhang C.Y.
        • Lowell B.B.
        The mitochondrial uncoupling-protein homologues.
        Nat Rev Mol Cell Biol. 2005; 6: 248-261
        • Fried S.K.
        • Bunkin D.A.
        • Greenberg A.S.
        Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
        J Clin Endocrinol Metab. 1998; 83: 847-850
        • Fukuhara A.
        • Matsuda M.
        • Nishizawa M.
        • Segawa K.
        • Tanaka M.
        • Kishimoto K.
        • Matsuki Y.
        • Murakami M.
        • Ichisaka T.
        • Murakami H.
        • Watanabe E.
        • Takagi T.
        • Akiyoshi M.
        • Ohtsubo T.
        • Kihara S.
        • Yamashita S.
        • Makishima M.
        • Funahashi T.
        • Yamanaka S.
        • Hiramatsu R.
        • Matsuzawa Y.
        • Shimomura I.
        Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.
        Science. 2005; 307: 426-430
        • Shimomura I.
        • Funahashi T.
        • Takahashi M.
        • Maeda K.
        • Kotani K.
        • Nakamura T.
        • Yamashita S.
        • Miura M.
        • Fukuda Y.
        • Takemura K.
        • Tokunaga K.
        • Matsuzawa Y.
        Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.
        Nat Med. 1996; 2: 800-803
        • Steppan C.M.
        • Bailey S.T.
        • Bhat S.
        • Brown E.J.
        • Banerjee R.R.
        • Wright C.M.
        • Patel H.R.
        • Ahima R.S.
        • Lazar M.A.
        The hormone resistin links obesity to diabetes.
        Nature. 2001; 409: 307-312
        • Tilg H.
        • Moschen A.R.
        Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
        Nat Rev Immunol. 2006; 6: 772-783
        • Kanda H.
        • Tateya S.
        • Tamori Y.
        • Kotani K.
        • Hiasa K.
        • Kitazawa R.
        • Kitazawa S.
        • Miyachi H.
        • Maeda S.
        • Egashira K.
        • Kasuga M.
        MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
        J Clin Invest. 2006; 116: 1494-1505
        • Fain J.N.
        • Madan A.K.
        • Hiler M.L.
        • Cheema P.
        • Bahouth S.W.
        Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans.
        Endocrinology. 2004; 145: 2273-2282
        • Johnson P.R.
        • Hirsch J.
        Cellularity of adipose depots in six strains of genetically obese mice.
        J Lipid Res. 1972; 13: 2-11
        • Krotkiewski M.
        • Bjorntorp P.
        • Sjostrom L.
        • Smith U.
        Impact of obesity on metabolism in men and women.
        J Clin Invest. 1983; 72: 1150-1162
        • Coon P.J.
        • Rogus E.M.
        • Drinkwater D.
        • Muller D.C.
        • Goldberg A.P.
        Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.
        J Clin Endocrinol Metab. 1992; 75: 1125-1132
        • Gastaldelli A.
        • Miyazaki Y.
        • Pettiti M.
        • Matsuda M.
        • Mahankali S.
        • Santini E.
        • DeFronzo R.A.
        • Ferrannini E.
        Metabolic effects of visceral fat accumulation in type 2 diabetes.
        J Clin Endocrinol Metab. 2002; 87: 5098-5103
        • Racanelli V.
        • Rehermann B.
        The liver as an immunological organ.
        Hepatology. 2006; 43: S54-S62
        • Cai D.
        • Yuan M.
        • Frantz D.F.
        • Melendez P.A.
        • Hansen L.
        • Lee J.
        • Shoelson S.E.
        Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.
        Nat Med. 2005; 11: 183-190
        • Guebre-Xabier M.
        • Yang S.
        • Lin H.Z.
        • Schwenk R.
        • Krzych U.
        • Diehl A.M.
        Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage.
        Hepatology. 2000; 31: 633-640
        • Li Z.
        • Soloski M.J.
        • Diehl A.M.
        Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.
        Hepatology. 2005; 42: 880-885
        • Godfrey D.I.
        • Kronenberg M.
        Going both ways: immune regulation via CD1d-dependent NKT cells.
        J Clin Invest. 2004; 114: 1379-1388
        • Elinav E.
        • Pappo O.
        • Sklair-Levy M.
        • Margalit M.
        • Shibolet O.
        • Gomori M.
        • Alper R.
        • Thalenfeld B.
        • Engelhardt D.
        • Rabbani E.
        • Ilan Y.
        Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping.
        J Pathol. 2006; 209: 121-128
        • Fearnley G.R.
        • Vincent C.T.
        • Chakrabarti R.
        Reduction of blood fibrinolytic activity in diabetes mellitus by insulin.
        Lancet. 1959; 2: 1067
        • Grace C.S.
        • Goldrick R.B.
        Fibrinolysis and body bulid.
        J Atheroscler Res. 1968; 8: 705-719
        • Ogston D.
        • McAndrew G.M.
        Fibrinolysis in obesity.
        Lancet. 1964; 14: 1205-1207
        • Dandona P.
        • Aljada A.
        • Bandyopadhyay A.
        Inflammation: the link between insulin resistance, obesity and diabetes.
        Trends Immunol. 2004; 25: 4-7
        • Kern P.A.
        • Ranganathan S.
        • Li C.
        • Wood L.
        • Ranganathan G.
        Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.
        Am J Physiol Endocrinol Metab. 2001; 280: E745-E751
        • Dandona P.
        • Weinstock R.
        • Thusu K.
        • Abdel-Rahman E.
        • Aljada A.
        • Wadden T.
        Tumor necrosis factor-α in sera of obese patients: fall with weight loss.
        J Clin Endocrinol Metab. 1998; 83: 2907-2910
        • Vozarova B.
        • Weyer C.
        • Hanson K.
        • Tataranni P.A.
        • Bogardus C.
        • Pratley R.E.
        Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion.
        Obes Res. 2001; 9: 414-417
        • Wakabayashi I.
        Age-related change in relationship between body-mass index, serum sialic acid, and atherogenic risk factors.
        J Atheroscler Thromb. 1998; 5: 60-65
        • Pradhan A.D.
        • Manson J.E.
        • Rifai N.
        • Buring J.E.
        • Ridker P.M.
        C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
        JAMA. 2001; 286: 327-334
        • Hotamisligil G.S.
        • Shargill N.S.
        • Spiegelman B.M.
        Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.
        Science. 1993; 259: 87-91
        • Feinstein R.
        • Kanety H.
        • Papa M.Z.
        • Lunenfeld B.
        • Karasik A.
        Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.
        J Biol Chem. 1993; 268: 26055-26058
        • Mohanty P.
        • Ghanim H.
        • Hamouda W.
        • Aljada A.
        • Garg R.
        • Dandona P.
        Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.
        Am J Clin Nutr. 2002; 75: 767-772
        • Dhindsa S.
        • Tripathy D.
        • Mohanty P.
        • Ghanim H.
        • Syed T.
        • Aljada A.
        • Dandona P.
        Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-κB in mononuclear cells.
        Metabolism. 2004; 53: 330-334
        • Aljada A.
        • Ghanim H.
        • Mohanty P.
        • Syed T.
        • Bandyopadhyay A.
        • Dandona P.
        Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations.
        Am J Clin Nutr. 2004; 80: 51-57
        • Tripathy D.
        • Mohanty P.
        • Dhindsa S.
        • Syed T.
        • Ghanim H.
        • Aljada A.
        • Dandona P.
        Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects.
        Diabetes. 2003; 52: 2882-2887
        • Dandona P.
        • Mohanty P.
        • Ghanim H.
        • Aljada A.
        • Browne R.
        • Hamouda W.
        • Prabhala A.
        • Afzal A.
        • Garg R.
        The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation.
        J Clin Endocrinol Metab. 2001; 86: 355-362
        • Dandona P.
        • Mohanty P.
        • Hamouda W.
        • Ghanim H.
        • Aljada A.
        • Garg R.
        • Kumar V.
        Inhibitory effect of a two-day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations.
        J Clin Endocrinol Metab. 2001; 86: 2899-2902
        • Weisberg S.P.
        • Hunter D.
        • Huber R.
        • Lemieux J.
        • Slaymaker S.
        • Vaddi K.
        • Charo I.
        • Leibel R.L.
        • Ferrante Jr, A.W.
        CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
        J Clin Invest. 2006; 116: 115-124
        • Lee J.Y.
        • Sohn K.H.
        • Rhee S.H.
        • Hwang D.
        Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.
        J Biol Chem. 2001; 276: 16683-16689
        • Shi H.
        • Kokoeva M.V.
        • Inouye K.
        • Tzameli I.
        • Yin H.
        • Flier J.S.
        TLR4 links innate immunity and fatty acid-induced insulin resistance.
        J Clin Invest. 2006; 116: 3015-3025
        • Furukawa S.
        • Fujita T.
        • Shimabukuro M.
        • Iwaki M.
        • Yamada Y.
        • Nakajima Y.
        • Nakayama O.
        • Makishima M.
        • Matsuda M.
        • Shimomura I.
        Increased oxidative stress in obesity and its impact on metabolic syndrome.
        J Clin Invest. 2004; 114: 1752-1761
        • Ozcan U.
        • Cao Q.
        • Yilmaz E.
        • Lee A.H.
        • Iwakoshi N.N.
        • Ozdelen E.
        • Tuncman G.
        • Gorgun C.
        • Glimcher L.H.
        • Hotamisligil G.S.
        Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.
        Science. 2004; 306: 457-461
        • Summers S.A.
        Ceramides in insulin resistance and lipotoxicity.
        Prog Lipid Res. 2006; 45: 42-72
        • Gao Z.
        • Zhang X.
        • Zuberi A.
        • Hwang D.
        • Quon M.J.
        • Lefevre M.
        • Ye J.
        Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.
        Mol Endocrinol. 2004; 18: 2024-2034
        • Hotamisligil G.S.
        Inflammation and metabolic disorders.
        Nature. 2006; 444: 860-867
        • Shoelson S.E.
        • Lee J.
        • Goldfine A.B.
        Inflammation and insulin resistance.
        J Clin Invest. 2006; 116: 1793-1801
        • Yuan M.
        • Konstantopoulos N.
        • Lee J.
        • Hansen L.
        • Li Z.W.
        • Karin M.
        • Shoelson S.E.
        Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.
        Science. 2001; 293: 1673-1677
        • Arkan M.C.
        • Hevener A.L.
        • Greten F.R.
        • Maeda S.
        • Li Z.W.
        • Long J.M.
        • Wynshaw-Boris A.
        • Poli G.
        • Olefsky J.
        • Karin M.
        IKK-β links inflammation to obesity-induced insulin resistance.
        Nat Med. 2005; 11: 191-198
        • Hundal R.S.
        • Petersen K.F.
        • Mayerson A.B.
        • Randhawa P.S.
        • Inzucchi S.
        • Shoelson S.E.
        • Shulman G.I.
        Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
        J Clin Invest. 2002; 109: 1321-1326
        • Shoelson S.E.
        • Lee J.
        • Yuan M.
        Inflammation and the IKK β/IκB/NF-κB axis in obesity- and diet-induced insulin resistance.
        Int J Obes Relat Metab Disord. 2003; 27: S49-S52
        • Hirosumi J.
        • Tuncman G.
        • Chang L.
        • Gorgun C.Z.
        • Uysal K.T.
        • Maeda K.
        • Karin M.
        • Hotamisligil G.S.
        A central role for JNK in obesity and insulin resistance.
        Nature. 2002; 420: 333-336
        • Kaneto H.
        • Nakatani Y.
        • Miyatsuka T.
        • Kawamori D.
        • Matsuoka T.A.
        • Matsuhisa M.
        • Kajimoto Y.
        • Ichijo H.
        • Yamasaki Y.
        • Hori M.
        Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide.
        Nat Med. 2004; 10: 1128-1132
        • Aguirre V.
        • Uchida T.
        • Yenush L.
        • Davis R.
        • White M.F.
        The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).
        J Biol Chem. 2000; 275: 9047-9054
        • Aguirre V.
        • Werner E.D.
        • Giraud J.
        • Lee Y.H.
        • Shoelson S.E.
        • White M.F.
        Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action.
        J Biol Chem. 2002; 277: 1531-1537
        • Werner E.D.
        • Lee J.
        • Hansen L.
        • Yuan M.
        • Shoelson S.E.
        Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302.
        J Biol Chem. 2004; 279: 35298-35305
        • Gao Z.
        • Hwang D.
        • Bataille F.
        • Lefevre M.
        • York D.
        • Quon M.J.
        • Ye J.
        Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex.
        J Biol Chem. 2002; 277: 48115-48121
        • Muller S.
        • Martin S.
        • Koenig W.
        • Hanifi-Moghaddam P.
        • Rathmann W.
        • Haastert B.
        • Giani G.
        • Illig T.
        • Thorand B.
        • Kolb H.
        Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors.
        Diabetologia. 2002; 45: 805-812
        • Pickup J.C.
        • Mattock M.B.
        • Chusney G.D.
        • Burt D.
        NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.
        Diabetologia. 1997; 40: 1286-1292
        • Fernandez-Real J.M.
        • Broch M.
        • Vendrell J.
        • Gutierrez C.
        • Casamitjana R.
        • Pugeat M.
        • Richart C.
        • Ricart W.
        Interleukin-6 gene polymorphism and insulin sensitivity.
        Diabetes. 2000; 49: 517-520
        • Kopp H.P.
        • Kopp C.W.
        • Festa A.
        • Krzyzanowska K.
        • Kriwanek S.
        • Minar E.
        • Roka R.
        • Schernthaner G.
        Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1042-1047
        • Klover P.J.
        • Clementi A.H.
        • Mooney R.A.
        Interleukin-6 depletion selectively improves hepatic insulin action in obesity.
        Endocrinology. 2005; 146: 3417-3427
        • Klover P.J.
        • Zimmers T.A.
        • Koniaris L.G.
        • Mooney R.A.
        Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice.
        Diabetes. 2003; 52: 2784-2789
        • Kim H.J.
        • Higashimori T.
        • Park S.Y.
        • Choi H.
        • Dong J.
        • Kim Y.J.
        • Noh H.L.
        • Cho Y.R.
        • Cline G.
        • Kim Y.B.
        • Kim J.K.
        Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
        Diabetes. 2004; 53: 1060-1067
        • Wallenius V.
        • Wallenius K.
        • Ahren B.
        • Rudling M.
        • Carlsten H.
        • Dickson S.L.
        • Ohlsson C.
        • Jansson J.O.
        Interleukin-6-deficient mice develop mature-onset obesity.
        Nat Med. 2002; 8: 75-79
        • van Exel E.
        • Gussekloo J.
        • de Craen A.J.
        • Frolich M.
        • Bootsma-Van Der Wiel A.
        • Westendorp R.G.
        Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-plus study.
        Diabetes. 2002; 51: 1088-1092
        • Straczkowski M.
        • Kowalska I.
        • Nikolajuk A.
        • Krukowska A.
        • Gorska M.
        Plasma interleukin-10 concentration is positively related to insulin sensitivity in young healthy individuals.
        Diabetes Care. 2005; 28: 2036-2037
        • Esposito K.
        • Pontillo A.
        • Di Palo C.
        • Giugliano G.
        • Masella M.
        • Marfella R.
        • Giugliano D.
        Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.
        JAMA. 2003; 289: 1799-1804
        • Lumeng C.N.
        • Bodzin J.L.
        • Saltiel A.R.
        Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
        J Clin Invest. 2007; 117: 175-184
        • Schafer K.
        • Fujisawa K.
        • Konstantinides S.
        • Loskutoff D.J.
        Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice.
        FASEB J. 2001; 15: 1840-1842
        • Hotamisligil G.S.
        • Arner P.
        • Caro J.F.
        • Atkinson R.L.
        • Spiegelman B.M.
        Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance.
        J Clin Invest. 1995; 95: 2409-2415
        • Katsuki A.
        • Sumida Y.
        • Murashima S.
        • Murata K.
        • Takarada Y.
        • Ito K.
        • Fujii M.
        • Tsuchihashi K.
        • Goto H.
        • Nakatani K.
        • Yano Y.
        Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent diabetes mellitus.
        J Clin Endocrinol Metab. 1998; 83: 859-862
        • Bruun J.M.
        • Verdich C.
        • Toubro S.
        • Astrup A.
        • Richelsen B.
        Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-α.
        Eur J Endocrinol. 2003; 148: 535-542
        • Bernstein L.E.
        • Berry J.
        • Kim S.
        • Canavan B.
        • Grinspoon S.K.
        Effects of etanercept in patients with the metabolic syndrome.
        Arch Intern Med. 2006; 166: 902-908
        • Ofei F.
        • Hurel S.
        • Newkirk J.
        • Sopwith M.
        • Taylor R.
        Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
        Diabetes. 1996; 45: 881-885
        • Mohanty P.
        • Aljada A.
        • Ghanim H.
        • Hofmeyer D.
        • Tripathy D.
        • Syed T.
        • Al-Haddad W.
        • Dhindsa S.
        • Dandona P.
        Evidence for a potent anti-inflammatory effect of rosiglitazone.
        J Clin Endocrinol Metab. 2004; 89: 2728-2735
        • Di Gregorio G.B.
        • Yao-Borengasser A.
        • Rasouli N.
        • Varma V.
        • Lu T.
        • Miles L.M.
        • Ranganathan G.
        • Peterson C.A.
        • McGehee R.E.
        • Kern P.A.
        Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone.
        Diabetes. 2005; 54: 2305-2313
        • Uysal K.T.
        • Wiesbrock S.M.
        • Marino M.W.
        • Hotamisligil G.S.
        Protection from obesity-induced insulin resistance in mice lacking TNF-α function.
        Nature. 1997; 389: 610-614
        • Schreyer S.A.
        • Chua Jr, S.C.
        • LeBoeuf R.C.
        Obesity and diabetes in TNF-α receptor- deficient mice.
        J Clin Invest. 1998; 102: 402-411
        • Vazquez L.A.
        • Pazos F.
        • Berrazueta J.R.
        • Fernandez-Escalante C.
        • Garcia-Unzueta M.T.
        • Freijanes J.
        • Amado J.A.
        Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery.
        J Clin Endocrinol Metab. 2005; 90: 316-322
        • Matsuki T.
        • Horai R.
        • Sudo K.
        • Iwakura Y.
        IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions.
        J Exp Med. 2003; 198: 877-888
        • Lagathu C.
        • Yvan-Charvet L.
        • Bastard J.P.
        • Maachi M.
        • Quignard-Boulange A.
        • Capeau J.
        • Caron M.
        Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes.
        Diabetologia. 2006; 49: 2162-2173
        • Nunez N.P.
        • Oh W.J.
        • Rozenberg J.
        • Perella C.
        • Anver M.
        • Barrett J.C.
        • Perkins S.N.
        • Berrigan D.
        • Moitra J.
        • Varticovski L.
        • Hursting S.D.
        • Vinson C.
        Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation.
        Cancer Res. 2006; 66: 5469-5476
        • Spranger J.
        • Kroke A.
        • Mohlig M.
        • Hoffmann K.
        • Bergmann M.M.
        • Ristow M.
        • Boeing H.
        • Pfeiffer A.F.
        Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.
        Diabetes. 2003; 52: 812-817
        • Bajaj M.
        • Suraamornkul S.
        • Hardies L.J.
        • Pratipanawatr T.
        • DeFronzo R.A.
        Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients.
        Int J Obes Relat Metab Disord. 2004; 28: 783-789
        • Kaser S.
        • Kaser A.
        • Sandhofer A.
        • Ebenbichler C.F.
        • Tilg H.
        • Patsch J.R.
        Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro.
        Biochem Biophys Res Commun. 2003; 309: 286-290
        • Bokarewa M.
        • Nagaev I.
        • Dahlberg L.
        • Smith U.
        • Tarkowski A.
        Resistin, an adipokine with potent proinflammatory properties.
        J Immunol. 2005; 174: 5789-5795
        • Silswal N.
        • Singh A.K.
        • Aruna B.
        • Mukhopadhyay S.
        • Ghosh S.
        • Ehtesham N.Z.
        Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-κB-dependent pathway.
        Biochem Biophys Res Commun. 2005; 334: 1092-1101
        • Verma S.
        • Li S.H.
        • Wang C.H.
        • Fedak P.W.
        • Li R.K.
        • Weisel R.D.
        • Mickle D.A.
        Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction.
        Circulation. 2003; 108: 736-740
        • Reilly M.P.
        • Lehrke M.
        • Wolfe M.L.
        • Rohatgi A.
        • Lazar M.A.
        • Rader D.J.
        Resistin is an inflammatory marker of atherosclerosis in humans.
        Circulation. 2005; 111: 932-939
        • Schernthaner G.H.
        • Kopp H.P.
        • Krzyzanowska K.
        • Kriwanek S.
        • Koppensteiner R.
        • Schernthaner G.
        Soluble CD40L in patients with morbid obesity: significant reduction after bariatric surgery.
        Eur J Clin Invest. 2006; 36: 395-401
        • Kamei N.
        • Tobe K.
        • Suzuki R.
        • Ohsugi M.
        • Watanabe T.
        • Kubota N.
        • Ohtsuka-Kowatari N.
        • Kumagai K.
        • Sakamoto K.
        • Kobayashi M.
        • Yamauchi T.
        • Ueki K.
        • Oishi Y.
        • Nishimura S.
        • Manabe I.
        • Hashimoto H.
        • Ohnishi Y.
        • Ogata H.
        • Tokuyama K.
        • Tsunoda M.
        • Ide T.
        • Murakami K.
        • Nagai R.
        • Kadowaki T.
        Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.
        J Biol Chem. 2006; 281: 26602-26614
        • Festa A.
        • Williams K.
        • Tracy R.P.
        • Wagenknecht L.E.
        • Haffner S.M.
        Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type 2 diabetes.
        Circulation. 2006; 113: 1753-1759
        • Leinonen E.
        • Hurt-Camejo E.
        • Wiklund O.
        • Hulten L.M.
        • Hiukka A.
        • Taskinen M.R.
        Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes.
        Atherosclerosis. 2003; 166: 387-394
        • Pannacciulli N.
        • Cantatore F.P.
        • Minenna A.
        • Bellacicco M.
        • Giorgino R.
        • De Pergola G.
        C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women.
        Int J Obes Relat Metab Disord. 2001; 25: 1416-1420
        • McLaughlin T.
        • Abbasi F.
        • Lamendola C.
        • Liang L.
        • Reaven G.
        • Schaaf P.
        • Reaven P.
        Differentiation between obesity and insulin resistance in the association with C-reactive protein.
        Circulation. 2002; 106: 2908-2912
        • Kopp H.P.
        • Krzyzanowska K.
        • Mohlig M.
        • Spranger J.
        • Pfeiffer A.F.
        • Schernthaner G.
        Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women.
        Int J Obes (Lond). 2005; 29: 766-771
        • Chu N.V.
        • Kong A.P.
        • Kim D.D.
        • Armstrong D.
        • Baxi S.
        • Deutsch R.
        • Caulfield M.
        • Mudaliar S.R.
        • Reitz R.
        • Henry R.R.
        • Reaven P.D.
        Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.
        Diabetes Care. 2002; 25: 542-549
        • Hung Y.J.
        • Lin S.H.
        • Pei D.
        • Kuo S.W.
        • Hsieh C.H.
        • He C.T.
        • Hsing Lee C.
        • Fan S.C.
        • Sheu W.H.
        Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein.
        Metabolism. 2006; 55: 439-444
        • Yang R.Z.
        • Lee M.J.
        • Hu H.
        • Pollin T.I.
        • Ryan A.S.
        • Nicklas B.J.
        • Snitker S.
        • Horenstein R.B.
        • Hull K.
        • Goldberg N.H.
        • Goldberg A.P.
        • Shuldiner A.R.
        • Fried S.K.
        • Gong D.W.
        Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.
        PLoS Med. 2006; 3: e287
        • Jernas M.
        • Palming J.
        • Sjoholm K.
        • Jennische E.
        • Svensson P.A.
        • Gabrielsson B.G.
        • Levin M.
        • Sjogren A.
        • Rudemo M.
        • Lystig T.C.
        • Carlsson B.
        • Carlsson L.M.
        • Lonn M.
        Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression.
        FASEB J. 2006; 20: 1540-1542
        • Potter van Loon B.J.
        • Kluft C.
        • Radder J.K.
        • Blankenstein M.A.
        • Meinders A.E.
        The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance.
        Metabolism. 1993; 42: 945-949
        • Ma L.J.
        • Mao S.L.
        • Taylor K.L.
        • Kanjanabuch T.
        • Guan Y.
        • Zhang Y.
        • Brown N.J.
        • Swift L.L.
        • McGuinness O.P.
        • Wasserman D.H.
        • Vaughan D.E.
        • Fogo A.B.
        Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1.
        Diabetes. 2004; 53: 336-346
        • Chu J.W.
        • Abbasi F.
        • Lamendola C.
        • McLaughlin T.
        • Reaven G.M.
        • Tsao P.S.
        Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects.
        Diabet Vasc Dis Res. 2005; 2: 37-41
        • Primrose J.N.
        • Davies J.A.
        • Prentice C.R.
        • Hughes R.
        • Johnston D.
        Reduction in factor VII, fibrinogen and plasminogen activator inhibitor-1 activity after surgical treatment of morbid obesity.
        Thromb Haemost. 1992; 68: 396-399
        • Paquot N.
        • Castillo M.J.
        • Lefebvre P.J.
        • Scheen A.J.
        No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients.
        J Clin Endocrinol Metab. 2000; 85: 1316-1319
        • Dominguez H.
        • Storgaard H.
        • Rask-Madsen C.
        • Steffen Hermann T.
        • Ihlemann N.
        • Baunbjerg Nielsen D.
        • Spohr C.
        • Kober L.
        • Vaag A.
        • Torp-Pedersen C.
        Metabolic and vascular effects of tumor necrosis factor-α blockade with etanercept in obese patients with type 2 diabetes.
        J Vasc Res. 2005; 42: 517-525
        • Jiang C.
        • Ting A.T.
        • Seed B.
        PPAR-γ agonists inhibit production of monocyte inflammatory cytokines.
        Nature. 1998; 391: 82-86
        • Ricote M.
        • Li A.C.
        • Willson T.M.
        • Kelly C.J.
        • Glass C.K.
        The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation.
        Nature. 1998; 391: 79-82
        • Aljada A.
        • Garg R.
        • Ghanim H.
        • Mohanty P.
        • Hamouda W.
        • Assian E.
        • Dandona P.
        Nuclear factor-κB suppressive and inhibitor-κB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an anti-inflammatory action?.
        J Clin Endocrinol Metab. 2001; 86: 3250-3256
        • Ghanim H.
        • Garg R.
        • Aljada A.
        • Mohanty P.
        • Kumbkarni Y.
        • Assian E.
        • Hamouda W.
        • Dandona P.
        Suppression of nuclear factor-κB and stimulation of inhibitor κB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese.
        J Clin Endocrinol Metab. 2001; 86: 1306-1312
        • Yki-Jarvinen H.
        Thiazolidinediones.
        N Engl J Med. 2004; 351: 1106-1118
        • Ialenti A.
        • Grassia G.
        • Di Meglio P.
        • Maffia P.
        • Di Rosa M.
        • Ianaro A.
        Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway.
        Mol Pharmacol. 2005; 67: 1620-1628
        • Pascual G.
        • Fong A.L.
        • Ogawa S.
        • Gamliel A.
        • Li A.C.
        • Perissi V.
        • Rose D.W.
        • Willson T.M.
        • Rosenfeld M.G.
        • Glass C.K.
        A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ.
        Nature. 2005; 437: 759-763
        • Belfort R.
        • Harrison S.A.
        • Brown K.
        • Darland C.
        • Finch J.
        • Hardies J.
        • Balas B.
        • Gastaldelli A.
        • Tio F.
        • Pulcini J.
        • Berria R.
        • Ma J.Z.
        • Dwivedi S.
        • Havranek R.
        • Fincke C.
        • DeFronzo R.
        • Bannayan G.A.
        • Schenker S.
        • Cusi K.
        A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
        N Engl J Med. 2006; 355: 2297-2307
        • Weitz-Schmidt G.
        Statins as anti-inflammatory agents.
        Trends Pharmacol Sci. 2002; 23: 482-486
        • Freeman D.J.
        • Norrie J.
        • Sattar N.
        • Neely R.D.
        • Cobbe S.M.
        • Ford I.
        • Isles C.
        • Lorimer A.R.
        • Macfarlane P.W.
        • McKillop J.H.
        • Packard C.J.
        • Shepherd J.
        • Gaw A.
        Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.
        Circulation. 2001; 103: 357-362
        • Baron S.H.
        Salicylates as hypoglycemic agents.
        Diabetes Care. 1982; 5: 64-71
        • Ebstein W.
        Zur therapie des diabetes mellitus, insbesondere über die Anwendung des salicylsauren natron bei demselben.
        Berlin KlinWochenschrift. 1876; 13: 337-340
        • Reid J.
        • Macdougall A.I.
        • Andrews M.M.
        On the efficacy of salicylate in treating diabetes mellitus.
        Br Med J. 1957; 2: 1071-1074
        • Williamson R.
        On the treatment of glycosuria and diabetes mellitus with sodium salicylate.
        Br Med J. 1901; 1: 760-762
        • Yin M.J.
        • Yamamoto Y.
        • Gaynor R.B.
        The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(κ)B kinase-β.
        Nature. 1998; 396: 77-80
        • Kopp E.
        • Ghosh S.
        Inhibition of NF-κB by sodium salicylate and aspirin.
        Science. 1994; 265: 956-959
        • Pierce J.W.
        • Read M.A.
        • Ding H.
        • Luscinskas F.W.
        • Collins T.
        Salicylates inhibit IκB-α phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration.
        J Immunol. 1996; 156: 3961-3969
        • Netea M.G.
        • Joosten L.A.
        • Lewis E.
        • Jensen D.R.
        • Voshol P.J.
        • Kullberg B.J.
        • Tack C.J.
        • van Krieken H.
        • Kim S.H.
        • Stalenhoef A.F.
        • van de Loo F.A.
        • Verschueren I.
        • Pulawa L.
        • Akira S.
        • Eckel R.H.
        • Dinarello C.A.
        • van den Berg W.
        • van der Meer J.W.
        Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.
        Nat Med. 2006; 12: 650-656
        • Banerjee R.R.
        • Rangwala S.M.
        • Shapiro J.S.
        • Rich A.S.
        • Rhoades B.
        • Qi Y.
        • Wang J.
        • Rajala M.W.
        • Pocai A.
        • Scherer P.E.
        • Steppan C.M.
        • Ahima R.S.
        • Obici S.
        • Rossetti L.
        • Lazar M.A.
        Regulation of fasted blood glucose by resistin.
        Science. 2004; 303: 1195-1198
        • Dong Z.M.
        • Gutierrez-Ramos J.C.
        • Coxon A.
        • Mayadas T.N.
        • Wagner D.D.
        A new class of obesity genes encodes leukocyte adhesion receptors.
        Proc Natl Acad Sci U S A. 1997; 94: 7526-7530
        • Perreault M.
        • Marette A.
        Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.
        Nat Med. 2001; 7: 1138-1143
        • Kawazoe Y.
        • Naka T.
        • Fujimoto M.
        • Kohzaki H.
        • Morita Y.
        • Narazaki M.
        • Okumura K.
        • Saitoh H.
        • Nakagawa R.
        • Uchiyama Y.
        • Akira S.
        • Kishimoto T.
        Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation.
        J Exp Med. 2001; 193: 263-269
        • Ryan A.S.
        • Nicklas B.J.
        Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women.
        Diabetes Care. 2004; 27: 1699-1705
        • Roberts C.K.
        • Won D.
        • Pruthi S.
        • Kurtovic S.
        • Sindhu R.K.
        • Vaziri N.D.
        • Barnard R.J.
        Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors.
        J Appl Physiol. 2006; 100: 1657-1665
        • Oberbach A.
        • Tonjes A.
        • Kloting N.
        • Fasshauer M.
        • Kratzsch J.
        • Busse M.W.
        • Paschke R.
        • Stumvoll M.
        • Bluher M.
        Effect of a 4-week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance.
        Eur J Endocrinol. 2006; 154: 577-585
        • Haffner S.M.
        • Greenberg A.S.
        • Weston W.M.
        • Chen H.
        • Williams K.
        • Freed M.I.
        Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus.
        Circulation. 2002; 106: 679-684
        • Jung H.S.
        • Youn B.S.
        • Cho Y.M.
        • Yu K.Y.
        • Park H.J.
        • Shin C.S.
        • Kim S.Y.
        • Lee H.K.
        • Park K.S.
        The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus.
        Metabolism. 2005; 54: 314-320
        • Akbar D.H.
        Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome.
        Endocrine. 2003; 20: 215-218
        • Drzewoski J.
        • Zurawska-Klis M.
        Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-α plasma levels in individuals with type 2 diabetes mellitus.
        Curr Med Res Opin. 2006; 22: 1921-1926
        • Desfaits A.C.
        • Serri O.
        • Renier G.
        Normalization of plasma lipid peroxides, monocyte adhesion, and tumor necrosis factor-α production in NIDDM patients after gliclazide treatment.
        Diabetes Care. 1998; 21: 487-493