Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.

Douglas Osei-Hyiaman, Jie Liu, Liang Zhou, Grzegorz Godlewski, Judith Harvey-White, Won-il Jeong, Sándor Bátkai, Giovanni Marsicano, Beat Lutz, Christoph Buettner, George Kunos
J. Clin. Invest.. 2008-09-02; 118(9): 3160-3169
DOI: 10.1172/jci34827

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1. J Clin Invest. 2008 Sep;118(9):3160-9. doi: 10.1172/JCI34827.

Hepatic CB1 receptor is required for development of diet-induced steatosis,
dyslipidemia, and insulin and leptin resistance in mice.

Osei-Hyiaman D(1), Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai
S, Marsicano G, Lutz B, Buettner C, Kunos G.

Author information:
(1)Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and
Alcoholism, NIH, Bethesda, Maryland, USA.

Comment in
Hepatology. 2008 Dec;48(6):2080-2.

Diet-induced obesity is associated with fatty liver, insulin resistance, leptin
resistance, and changes in plasma lipid profile. Endocannabinoids have been
implicated in the development of these associated phenotypes, because mice
deficient for the cannabinoid receptor CB1 (CB1-/-) do not display these changes
in association with diet-induced obesity. The target tissues that mediate these
effects, however, remain unknown. We therefore investigated the relative role of
hepatic versus extrahepatic CB1 receptors in the metabolic consequences of a
high-fat diet, using liver-specific CB1 knockout (LCB1-/-) mice. LCB1(-/-) mice
fed a high-fat diet developed a similar degree of obesity as that of wild-type
mice, but, similar to CB1(-/-) mice, had less steatosis, hyperglycemia,
dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a
high-fat diet. CB1 agonist-induced increase in de novo hepatic lipogenesis and
decrease in the activity of carnitine palmitoyltransferase-1 and total energy
expenditure were absent in both CB1(-/-) and LCB1(-/-) mice. We conclude that
endocannabinoid activation of hepatic CB1 receptors contributes to the
diet-induced steatosis and associated hormonal and metabolic changes, but not to
the increase in adiposity, observed with high-fat diet feeding. Theses studies
suggest that peripheral CB1 receptors could be selectively targeted for the
treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order
to minimize the neuropsychiatric side effects of nonselective CB1 blockade during
treatment of obesity-associated conditions.

DOI: 10.1172/JCI34827
PMCID: PMC2491458
PMID: 18677409 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus