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

Boon, Mariëtte R.; Kooijman, Sander; Dam, Anke; Pelgrom, Leonard R.; Berbée, Jimmy F.P.; Visseren, Cheryl A. R.; Aggele, Robin C. van; Hoek, Anita M. van den; Sips, Hetty C M; Lombès, Marc; Havekes, Louis M.; Tamsma, Jouke T.; Guigas, Bruno; Meijer, Onno C.; Jukema, J. Wouter; Rensen, Patrick C.N.

doi:10.1096/fj.13-247643

Cited by 90 publications

(69 citation statements)

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“…High plasmatic levels of endocannabinoids have been associated with increased cardiometabolic risk, visceral WAT accumulation, and type 2 diabetes in obese patients ( 19 ). Genetic impairment of CB1 receptors selectively in neurons of the brain and sympathetic nervous system (SNS) enhances energy expenditure by the BAT ( 20 ), and very recent evidence suggests an inhibitory role of prejunctional CB1 on brown adipocyte glucose utilization ( 21 ), thermogenesis, and lipid droplet formation ( 22 ). Furthermore, CB1 blockade in Sim1-expressing neurons of the paraventricular nucleus of the hypothalamus enhances energy expenditure during high-fat diet feeding ( 23 ).…”

Section: Experimental Animals and Dietsmentioning

confidence: 99%

“…While there are several examples of reports [summarized in ( 19 )] pointing to an autocrine role of endocannabinoids and CB1 receptors on white adipocytes, also facilitating, among others, their transformation into beige adipocytes ( 25,26 ), evidence for a similar role in brown adipocytes is still scant . Through the use of a peripherally restricted CB1 antagonist in vivo, and of T37i brown adipocyte-like cells in vitro, Boon et al ( 22 ) very recently suggested that some of the above effects of CB1 blockade in the BAT, and in particular the stimulation of uncoupled respiration, may be exerted postjunctionally and directly on brown adipocytes, most likely by enhancing cyclic AMP/PKA signaling induced by ␤ 3-adrenoceptor activation. However, the question of whether exposure to cold, via sympathetic stimulation of ␤ 3-adrenoceptors in brown adipocytes, enhances endocannabinoid levels in BAT has not been tested so far.…”

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confidence: 99%

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Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

Krott

Piscitelli

Heine

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org related chronic metabolic diseases. The natural function of BAT is to combust energy from high-caloric nutrients to defend the body against cold environments ( 4 ). The ability to burn energy-dense triglycerides as fuels for heat production could enable BAT to diminish hypertrophic white adipose tissue (WAT) depots, a prerequisite for the prevention of metabolic lifestyle diseases ( 5, 6 ). In humans, BAT activity, determined by positron emission tomographycomputed tomography (PET-CT), is positively correlated with BAT mass ( 1-3 ), BAT activation status ( 2 ), and environmental factors such as low temperatures ( 7 ). Repeated cold exposure leads to increased BAT activity ( 8, 9 ), a condition that is associated with a self-reported decrease in sensitivity to cold. The thermogenic process is dependent on the presence of uncoupling protein 1 (UCP1), a protein located in the inner membrane of mitochondria that is able to separate electron transport in the respiratory chain from the production of energy in the form of ATP. The heat generated by this exothermic reaction is transported via the blood circulation system to maintain body temperature ( 10 ). Low BAT activity in humans correlates with ageing and obesity ( 2, 11 ), suggesting a causal link between decreased BAT activity, weight gain, and the development of metabolic diseases. In this context, channeling fatty acids and triglycerides into BAT could attenuate deleterious effects that saturated fatty acids cause by ectopic lipid accumulation in the liver or heart . In fact, up to 90% of energy for heat production is derived from fatty acids that are delivered by triglyceriderich lipoproteins ( 4, 10, 12 ). These latter are hepatic VLDLs Abstract The endocannabinoids and their main receptor, cannabinoid type-1 (CB1), suppress intracellular cyclic AMP levels and have emerged as key players in the control of energy metabolism. CB1 agonists and blockers have been reported to infl uence the thermogenic function of white and brown adipose tissue (WAT and BAT), affecting body weight through the inhibition and stimulation of energy expenditure, respectively. The purpose of the current study was to investigate the regulation of the endocannabinoid system in WAT and BAT following exposure to either cold or specifi c agonism of ␤ 3-adrenoceptors using CL316,243 (CL), conditions known to cause BAT activation and WAT browning. To address this question, we performed quantitative PCRbased mRNA profi ling of genes important for endocannabinoid synthesis , degradation, and signaling, and determined endocannabinoid levels by LC-MS in WAT and BAT of control, cold-exposed, and CL-treated wild-type mice as well as primary brown adipocytes. Treatment with CL and exposure to cold caused an upregulation of endocannabinoid levels and biosynthetic enzymes in WAT. Acute ␤ 3-adrenoceptor activation increased endocannabinoids and a subset of genes of biosynthesis in BAT and primary brown adipocytes. We suggest that the cold-mediated ...

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Section: Experimental Animals and Dietsmentioning

confidence: 99%

mentioning

confidence: 99%

Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

Krott

Piscitelli

Heine

et al. 2016

Journal of Lipid Research

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“…Upon randomization and at 4-week intervals during treatment, blood samples were collected after a 6-h fast and assayed for levels of TGs, total cholesterol (TC), and free fatty acids (FFA), as described previously (11,12).…”

Section: Determination Of Plasma Parametersmentioning

confidence: 99%

“…Pieces of snap-frozen mouse tissue (~50 mg) or T37i cells (grown in 3.8 cm 2 wells) were lysed, protein was isolated, and Western blots were performed as previously described (11). Primary antibodies and dilutions are listed in Supplementary Table 1.…”

Section: Western Blot Analysismentioning

confidence: 99%

Salsalate Activates Brown Adipose Tissue in Mice

et al. 2014

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Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the current study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high-fat diet–induced obesity. We found that salsalate attenuated and reversed high-fat diet–induced weight gain, in particular fat mass accumulation, improved glucose tolerance, and lowered plasma triglyceride levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[3H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT, and increased rectal temperature, all pointing to more active BAT. The treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by the inhibition of cAMP-dependent protein kinase (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients.

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“…These effects were shown to be mediated by both peripheral CB1 (5) and CB1 located in the central nervous system (CNS) (4).…”

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The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue

et al. 2015

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Recently, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed. Its role in the human metabolism is unknown but could be substantial. Inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) has been associated with activation of BAT thermogenesis and weight loss in mice and rats. The role of peripheral and central CB1 in the activation of BAT merits further investigation. Here we developed a technique for quantifying CB1 in BAT by PET. Methods: Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the ra-to BAT in vivo and in vitro was assessed in rats by PET. Results: We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of 18 F-FMPEP-d 2 in vivo, indicating high CB1 density. WAT deposits were negative for 18 F-FMPEP-d 2 , consistent with the immunofluorescent staining and in vitro results. Conclusion: 18 F-FMPEP-d 2 PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.Key Words: brown adipose tissue; cannabinoid 1 receptor; 18 F-FMPEP-d 2 ; positron emission tomography J Nucl Med 2015; 56:1937 56: -1941 56: DOI: 10.2967 Recent ly, the existence of significant deposits of brown adipose tissue (BAT) in human adults was confirmed (1). Its influence on the whole-body metabolism and energy expenditure in humans is currently unknown, but based on extensive experience in rodents it could be substantial (2). Quantitative noninvasive measurements of cold activated BAT glucose utilization amount to 12.2 mmol/100 g of BAT/min, and given that the primary energy source for BAT is fatty acids, the true energy expenditure may be higher (1). Consequently, pharmaceutical means for inducing subcutaneous white adipose tissue (WAT) to BAT conversion (browning) as well as BAT activation are pursued for the treatment of obesity.It has been shown that chronic inhibition of the cannabinoid receptor-1 (CB1) by the antagonist rimonabant (SR141716) is associated with activation of BAT thermogenesis and weight loss in mice and rats (3,4). These effects were shown to be mediated by both peripheral CB1 (5) and CB1 located in the central nervous system (CNS) (4).Furthermore, chronic treatment by rimonabant induced an increase in uncoupling protein-1 (UCP-1) in WAT and initiated a transdifferentiation into a brown fat phenotype (6). Clearly, the role of peripheral and central CB1 in the activation of BAT merits further investigation.However, the clinical translation of these interesting results has been hampered by the lack of methodologies for the noninvasive in v...

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

Cited by 90 publications

References 52 publications

Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

Salsalate Activates Brown Adipose Tissue in Mice

The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue

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