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Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity

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Author: Boon, M.R. · Kooijman, S. · Dam, A.D. van · Pelgrom, L.R. · Berbée, J.F.P. · Visseren, C.A.R. · Aggele, R.C. van · Hoek, A.M. van den · Sips, H.C.M. · Lombès, M. · Havekes, L.M. · Tamsma, J.T. · Guigas, B. · Meijer, O.C. · Jukema, J.W. · Rensen, P.C.N.
Type:article
Date:2014
Source:FASEB Journal, 12, 28, 5361-5375
Identifier: 521630
doi: DOI:10.1096/fj.13-247643
Keywords: Biology · Rimonabant · Sympathetic nervous system · Uncoupling protein 1 · Adrenergic receptor · Am 6545 · Cannabinoid 1 receptor · Cannabinoid 1 receptor antagonist · Cyclic AMP · Fat droplet · Lipoprotein · Triacylglycerol · Unclassified drug · Adrenergic system · Animal experiment · Animal model · Animal tissue · Appetite · Brown adipocyte · Alorimetry · Controlled study · Diet induced obesity · Dyslipidemia · Energy expenditure · Energy metabolism · Food intake · In vitro study · In vivo study · Lipid analysis · Lipid storage · Lipolysis · Lipoprotein metabolism · Male · Mouse · Nonhuman · Oxygen consumption · Physical activity · Thermogenesis · Triacylglycerol blood level · Weight change · Weight reduction · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

Abstract

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.