Endocannabinoid signal in the gut controls dietary fat intake

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 31; pp. 12904 - 12908
• Main Authors: DiPatrizio, Nicholas V, Astarita, Giuseppe, Schwartz, Gary, Li, Xiaosong, Piomelli, Daniele
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.08.2011; National Acad Sciences
• Series: From the Cover
• Subjects: Amidohydrolases - metabolism; Animals; antagonists; Benzyl Compounds - pharmacology; Biological Sciences; Body fat; brain; Brain - drug effects; Brain - metabolism; Cannabinoid Receptor Modulators - metabolism; Cannulae; Corn oil; Diet; Dietary Fats - administration & dosage; Dietary Fats - metabolism; drugs; duodenum; Eating - drug effects; Eating - physiology; Endocannabinoids; energy balance; enzyme activity; Fat intake; food intake; foods; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Intestine, Small - drug effects; Intestine, Small - metabolism; Lipids; Lipids - analysis; Liquids; Male; metabolism; Phospholipase D - metabolism; Piperidines - pharmacology; Pyrazoles - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Receptors; Rimonabant; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Stomach; T cell receptors; Vagotomy; vagus nerve
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1104675108

Oral sensory signals drive dietary fat intake, but the neural mechanisms underlying this process are largely unknown. The endocannabinoid system has gained recent attention for its central and peripheral roles in regulating food intake, energy balance, and reward. Here, we used a sham-feeding paradigm, which isolates orosensory from postingestive influences of foods, to examine whether endocannabinoid signaling participates in the positive feedback control of fat intake. Sham feeding a lipid-based meal stimulated endocannabinoid mobilization in the rat proximal small intestine by altering enzymatic activities that control endocannabinoid metabolism. This effect was abolished by surgical transection of the vagus nerve and was not observed in other peripheral organs or in brain regions that control feeding. Sham feeding of a nutritionally complete liquid meal produced a similar response to that of fat, whereas protein or carbohydrate alone had no such effect. Local infusion of the CB₁-cannabinoid receptor antagonist, rimonabant, into the duodenum markedly reduced fat sham feeding. Similarly to rimonabant, systemic administration of the peripherally restricted CB₁-receptor antagonist, URB 447, attenuated sham feeding of lipid. Collectively, the results suggest that the endocannabinoid system in the gut exerts a powerful regulatory control over fat intake and might be a target for antiobesity drugs.