Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways.
The endocannabinoids are lipid-derived signaling molecules that control feeding and energy balance by activating CB1-type cannabinoid receptors in the brain and peripheral tissues. Previous studies have shown that oral exposure to dietary fat stimulates endocannabinoid signaling in the rat small intestine, which provides positive feedback that drives further food intake and preference for fat-rich foods. We now describe an unexpectedly broader role for cholinergic signaling of the vagus nerve in the production of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the small intestine. We show that food deprivation increases levels of 2-AG and its lipid precursor, 1,2-diacylglycerol, in rat jejunum mucosa in a time-dependent manner. This response is abrogated by surgical resection of the vagus nerve or pharmacological blockade of small intestinal subtype-3 muscarinic acetylcholine (m3 mAch) receptors, but not inhibition of subtype-1 muscarinic acetylcholine (m1 mAch). We further show that blockade of peripheral CB1 receptors or intestinal m3 mAch receptors inhibits refeeding in fasted rats. The results suggest that food deprivation stimulates 2-AG-dependent CB1 receptor activation through a mechanism that requires efferent vagal activation of m3 mAch receptors in the jejunum, which, in turn, may promote feeding after a fast.
Division of Biomedical Sciences, University of California, Riverside, School of Medicine, Riverside, California; Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Nicholas V
NV
DiPatrizio
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Miki
M
Igarashi
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Vidya
V
Narayanaswami
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Conor
C
Murray
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Joseph
J
Gancayco
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Amy
A
Russell
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California;
Kwang-Mook
KM
Jung
Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California; Department of Pharmacology, University of California, Irvine, School of Medicine, Irvine, California; Department of Biological Chemistry, University of California, Irvine, School of Medicine, Irvine, California; and Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy piomelli@uci.edu.
Daniele
D
Piomelli
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis* / Q000235:genetics; D001285:Atropine / Q000494:pharmacology; D063388:Endocannabinoids / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005508:Food Deprivation / Q000502:physiology*; D005989:Glycerides / Q000096:biosynthesis* / Q000235:genetics; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000077403:Orlistat; D010276:Parasympatholytics / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors
C551825:AM6545; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D007783:Lactones; D009025:Morpholines; D010276:Parasympatholytics; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D001285:Atropine; C094503:glyceryl 2-arachidonate; D000077403:Orlistat
cannabinoid receptor type 1 (CB1); cholinergic receptor; endocannabinoid; gut-brain; vagus nerve