Gastroenterology
Volume 137, Issue 1 , Pages 18-19, July 2009

Intestinal Lipids as Signaling Molecules

published online 01 June 2009.

Article Outline

 

Obesity is a major problem in modern society, in part because of overconsumption of energy-dense and fatty foods.1 Most adults consume 60–150 g/d of fat, containing mainly triglycerides (>90%). Digestion of triglycerides is initiated by lingual and gastric lipases, but is mainly controlled by pancreatic lipase in the proximal small intestine. Long-chain fatty acids (>12 carbon atoms) and monoacylglycerols derived from digestion of triglycerides bind to intestinal fatty acid–binding protein in enterocytes, are transported to the endoplasmic reticulum, and reesterified into triglycerides. Cholesterol is esterified by cholesterol acyltransferase. Newly synthesized triglycerides and cholesterol esters are coated by phospholipids and apolipoproteins forming chylomicrons, which are delivered into the systemic circulation via the mesenteric lymphatics and thoracic duct. Thus, long-chain fatty acids reach muscle and adipose tissue through the systemic circulation before entering the liver. In contrast, medium-chain fatty acids (≤10 carbons) reach the liver directly via the portal vein. In addition to providing calories for storage and metabolism, dietary fat has profound effects on gastrointestinal function. Dietary fat slows gastric motility and emptying. Administration of lipids directly into the duodenum inhibits food intake in rodents and humans, likely through sensory vagal nerves from the gut to the nucleus of the solitary tract in the brain stem.2 Recently, the importance of fatty acid metabolites as signals for regulation of feeding and glucose homeostasis has been highlighted.3, 4

Schwartz et al3 examined the role of oleoylethanolamide (OEA) (Figure 1A). a member of the fatty acid ethanolamide family, which includes palmitoylethanolamide and anandamide. The latter is a ligand for the cannabinoid 1 receptor, a target of the anti-obesity drug, rimonabant.5 OEA is synthesized by mucosal cells of the upper intestine in response to feeding and suppressed by fasting. Earlier studies showed that systemic injection of OEA inhibited food intake in rodents, specifically by prolonging the interval between meals.6 Although mice lacking peroxisome proliferator activated receptor (PPAR)-α were insensitive to OEA, the molecular mechanisms linking OEA production in the gut to regulation of feeding were unclear.7 Schwartz et al3 showed that infusion of a lipid emulsion or oleic acid into the duodenum generated OEA locally, whereas infusion of protein or carbohydrate did not. Intraduodenal infusion of OEA decreased food intake. Plasma-derived oleic acid, on the other hand, did not increase OEA levels in the intestine, emphasizing that OEA was generated locally.3 Another key finding was that mice lacking the membrane glycoprotein CD36 did not manifest the satiety action of OEA.3 CD36 is located on the luminal surface of enterocytes in duodenum and jejunum, binds and transports fatty acids across the plasma membrane, and is therefore a plausible cellular mediator of OEA. Consistent with previous studies, PPAR-α–null mice did not respond to the anorexic action of OEA.7 Overall, these results identify OEA as an important lipid signal linking dietary fat to regulation of feeding. However, short-term changes in feeding were examined, and there are questions about the pathways downstream of PPAR-α and how these control feeding behavior, nutrient absorption, and energy balance. It is unknown whether OEA interacts with gut hormones. Moreover, it remains to be ascertained whether the gut lipid-sensing pathway in rodents involving OEA, CD36, and PPAR-α is present in humans, and whether these molecules can be targeted specifically for the treatment of obesity.

  • View full-size image.
  • Figure 1. 

    (A) Oleoylethanolamide (OEA) is generated from dietary triglycerides and regulates satiety and lipid metabolism. (B) Insulin normally suppresses hepatic glucose production and increases glucose uptake by muscle and fat. Long-chain fatty acyl coenzyme A (LCFACoA) is generated from dietary fatty acids in the upper intestine and stimulates hepatic glucose production.

A connection between lipid sensing in the brain and peripheral glucose metabolism has been described previously.8 In rodents, administration of oleic acid in the hypothalamus or direct inhibition of carnitine palmitoyl-transferase-1 decreased hepatic glucose production.8 This effect was abolished by vagotomy, leading to the hypothesis that fatty acids play a crucial role in glucose homeostasis.8 Wang et al4 assessed glucose fluxes during fasting, intraduodenal lipid infusion, and pancreatic clamp. Infusion of fat into the duodenum increased long-chain fatty acyl coenzyme A (LCFACoA) levels locally without affecting nutrient absorption (Figure 1B). Interesting, the rise in intestinal LCFACoAs enhanced insulin sensitivity in the liver, but not muscle and fat (Figure 1B). To test whether the formation of LCFACoAs was responsible for increasing insulin action in the liver, triascin-C, an inhibitor of acyl-CoA synthetase, was co-infused with lipids into the duodenum. As predicted, the stimulation of glucose production was prevented by triascin-C, confirming a critical role of intestinal LCFACoA as a mediator of hepatic insulin action. Next, the authors studied the role of gut–brain stem innervation. The insulin-sensitizing effect of LCFACoAs was abolished after pharmacologic disruption of glutaminergic vagal innervation from the gut to the nucleus of the tractus solitarius. Similarly, sensory denervation of the intestine or hepatic vagotomy prevented the ability of intraduodenal LCFACoAs to increase hepatic insulin action. However, in contrast with rats on a regular (low-fat) chow diet, those on a high-fat diet for 3 days failed to respond to intraduodenal lipid infusion. Whether this indicates a link between dietary fat and insulin resistance is uncertain. Moreover, the work by Wang et al does not illuminate our knowledge of the cells in the upper intestine that produce or respond to LCFACoAs, how the vagus transmits the LCFACoA signal, whether gut hormones are involved, and to what extent the results in rodents apply to physiologic or disease states.

Nevertheless, the revelation that intestinal fatty acid metabolites control feeding and insulin sensitivity is a crucial step toward unraveling the connection between dietary fat and metabolic signaling. These studies provide a framework for further investigation into the connection between nutrients and eating disorders, obesity, and diabetes. An area that could benefit from these results is how Roux-en-Y gastric bypass (RYGB) surgery increases satiety, decreases body fat, and improves diabetes.9 In addition to glucagon-like peptide-1, which is increased after RYGB and thought to improve diabetes, it is tempting to speculate that alterations in the levels of OEA, LCFACoAs, and other fatty acid metabolites may serve as signals in the gut–brain–liver axis to induce satiety and improve glucose homeostasis after RYGB.

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References 

  1. Bray GA, Paeratakul S, Popkin BM. Dietary fat and obesity: a review of animal, clinical and epidemiological studies. Physiol Behav. 2004;83:549–555
  2. Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition. 2000;16:866–873
  3. Schwartz GJ, Fu J, Astarita G, et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008;8:281–288
  4. Wang PY, Caspi L, Lam CK, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 2008;452:1012–1016
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  6. Rodríguez de Fonseca F, Navarro M, Gómez R, et al. An anorexic lipid mediator regulated by feeding. Nature. 2001;414:209–212
  7. Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003;425:90–93
  8. Lam TK, Schwartz GJ, Rossetti L, et al. Hypothalamic sensing of fatty acids. Nat Neurosci. 2005;8:579–584
  9. Kral JG, Näslund E. Surgical treatment of obesity. Nat Clin Pract Endocrinol Metab. 2007;3:574–583

PII: S0016-5085(09)00795-1

doi:10.1053/j.gastro.2009.05.030

Gastroenterology
Volume 137, Issue 1 , Pages 18-19, July 2009