Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.
Endogenous cannabinoids acting at CB(1) receptors stimulate appetite, and CB(1) antagonists show promise in the treatment of obesity. CB(1) (-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB(1) agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB(1). High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB(1) density, and basal rates of fatty acid synthesis, and the latter is reduced by CB(1) blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB(1) ligands. We conclude that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
Osei-Hyiaman
Douglas
D
National Institute on Alcohol Abuse & Alcoholism, NIH, Bethesda, Maryland 20892, USA.
DePetrillo
Michael
M
Pacher
Pál
P
Liu
Jie
J
Radaeva
Svetlana
S
Bátkai
Sándor
S
Harvey-White
Judith
J
Mackie
Ken
K
Offertáler
László
L
Wang
Lei
L
Kunos
George
G
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D063388:Endocannabinoids; D005227:Fatty Acids / Q000096:biosynthesis*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism
D001095:Arachidonic Acids; D022762:CCAAT-Enhancer-Binding Proteins; D063385:Cannabinoid Receptor Modulators; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D063388:Endocannabinoids; D005227:Fatty Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C078814:anandamide