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| Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity |
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| Author(s): Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G |
| Source: JOURNAL OF CLINICAL INVESTIGATION Volume: 115 Issue: 5 Pages: 1298-1305 Published: MAY 2005 |
| Times Cited: 290 References: 52 |
| Abstract: Endogenous cannabinoids acting at CB, receptors stimulate appetite, and CB, antagonists show promise in the treatment of obesity. CB1-/- 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 CB1 in mice increases the hepatic gene expression of the lipogenic transcription factor SR-EBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB1. High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB1 ligands. We conclude that anandamide acting at hepatic CBI contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. |
| Document Type: Article |
| Language: English |
| Reprint Address: Kunos, G (reprint author), NIAAA, NIH, 5625 Fishers Lane,MSC-9413, Bethesda, MD 20892 USA |
Addresses:
1. NIAAA, NIH, Bethesda, MD 20892 USA
2. Univ Washington, Dept Physiol, Seattle, WA 98195 USA
3. Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA |
| Publisher: AMER SOC CLINICAL INVESTIGATION INC, 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA |
| Subject Category: Medicine, Research & Experimental |
| IDS Number: 923KH |
| ISSN: 0021-9738 |
| DOI: 10.1172/JCI200523057 |
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