Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism.
Obesity. 2009-03-26; 17(8): 1641-1645
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1. Obesity (Silver Spring). 2009 Aug;17(8):1641-5. doi: 10.1038/oby.2009.84. Epub
2009 Mar 26.
Food intake-independent effects of CB1 antagonism on glucose and lipid
Cota D(1), Sandoval DA, Olivieri M, Prodi E, D’Alessio DA, Woods SC, Seeley RJ,
(1)Department of Psychiatry, University of Cincinnati, Genome Research Institute,
Cincinnati, Ohio, USA.
Overactivity of the endocannabinoid system (ECS) has been linked to abdominal
obesity and other risk factors for cardiovascular disease and type 2 diabetes.
Conversely, administration of cannabinoid receptor type 1 (CB1) antagonists
reduces adiposity in obese animals and humans. This effect is only in part
secondary to the anorectic action of CB1 agonists. In order to assess the actions
of CB1 antagonism on glucose homeostasis, diet-induced obese (DIO) rats received
the CB1 antagonist rimonabant (10 mg/kg, intraperitoneally (IP)) or its vehicle
for 4 weeks, or were pair-fed to the rimonabant-treated group for the same length
of time. Rimonabant treatment transiently reduced food intake, while inducing
body weight loss throughout the study. Rats receiving rimonabant had
significantly less body fat and circulating leptin compared to both vehicle and
pair-fed groups. Rimonabant, but not pair-feeding, also significantly decreased
circulating nonesterified fatty acid (NEFA) and triacylglycerol (TG) levels, and
reduced TG content in oxidative skeletal muscle. Although no effects were
observed during a glucose tolerance test (GTT), rimonabant restored insulin
sensitivity to that of chow-fed, lean controls during an insulin tolerance test
(ITT). Conversely, a single dose of rimonabant to DIO rats had no acute effect on
insulin sensitivity. These findings suggest that in diet-induced obesity, chronic
CB1 antagonism causes weight loss and improves insulin sensitivity by diverting
lipids from storage toward utilization. These effects are independent of the
anorectic action of the drug.
PMID: 19325539 [Indexed for MEDLINE]