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.
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