Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice.
Diabetologia. 2011-10-11; 54(12): 3121-3131
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1. Diabetologia. 2011 Dec;54(12):3121-31. doi: 10.1007/s00125-011-2302-6. Epub 2011
Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and
activates brown adipose tissue in diet-induced obese mice.
Bajzer M(1), Olivieri M, Haas MK, Pfluger PT, Magrisso IJ, Foster MT, Tschöp MH,
Krawczewski-Carhuatanta KA, Cota D, Obici S.
(1)Metabolic Diseases Institute, University of Cincinnati, 2140 East Galbraith
Road, Building B, Room 332, Cincinnati, OH 45237-1625, USA.
AIMS/HYPOTHESIS: We examined the physiological mechanisms by which cannabinoid
receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity
independent of its anorectic and weight-reducing effects, as well as the effects
of CB1 antagonism on brown adipose tissue (BAT) function.
METHODS: Three groups of diet-induced obese mice received for 1 month: vehicle;
the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After
measurements of body composition and energy expenditure, mice underwent
euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In
separate cohorts, we assessed insulin action in weight-reduced mice with
diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT
thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out
in order to study the requirement for the sympathetic nervous system in mediating
the effects of CB1 antagonism on BAT function.
RESULTS: Weight loss associated with chronic CB1 antagonism was accompanied by
increased energy expenditure, enhanced insulin-stimulated glucose utilisation,
and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was
significantly increased in white adipose tissue and BAT, whereas glycogen
synthesis was increased in liver, fat and muscle. Despite marked weight loss in
the mice, SR141716 treatment did not improve insulin-mediated suppression of
hepatic glucose production nor increase skeletal muscle glucose uptake.
Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and
insulin-mediated glucose uptake.
CONCLUSIONS/INTERPRETATION: Chronic CB1 antagonism markedly enhances
insulin-mediated glucose utilisation in DIO mice, independent of its anorectic
and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose
uptake reveals a novel role for CB1 receptors as regulators of glucose
PMID: 21987346 [Indexed for MEDLINE]