Title
Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity
Author
Boon, M.R.
Kooijman, S.
van Dam, A.D.
Pelgrom, L.R.
Berbée, J.F.P.
Visseren, C.A.R.
van Aggele, R.C.
van den Hoek, A.M.
Sips, H.C.M.
Lombès, M.
Havekes, L.M.
Tamsma, J.T.
Guigas, B.
Meijer, O.C.
Jukema, J.W.
Rensen, P.C.N.
Publication year
2014
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.
Subject
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
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
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DOI
https://doi.org/10.1096/fj.13-247643
TNO identifier
521630
ISSN
0892-6638
Source
FASEB Journal, 28 (12), 5361-5375
Document type
article