Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

Lucia M Krott,Fabiana Piscitelli,Markus Heine,Simona Borrino,Ludger Scheja,Cristoforo Silvestri,Joerg Heeren,Vincenzo Di Marzo

doi:10.1194/jlr.m065227

Lucia M Krott, Fabiana Piscitelli + Show 6 more

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https://doi.org/10.1194/jlr.m065227

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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 influence 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 specific agonism of β3-adrenoceptors using CL316,243 (CL), conditions known to cause BAT activation and WAT browning. To address this question, we performed quantitative PCR-based mRNA profiling 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 β3-adrenoceptor activation increased endocannabinoids and a subset of genes of biosynthesis in BAT and primary brown adipocytes. We suggest that the cold-mediated increase in endocannabinoid tone is part of autocrine negative feed-back mechanisms controlling β3-adrenoceptor-induced BAT activation and WAT browning.

Highlights

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
We have shown for the first time that activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) in mice cause upregulation of endocannabinoid levels and, presumably, endocannabinoid signaling via CB1 receptors in these tissues
Given that CB1 receptor stimulation leads to a decrease of cyclic AMP signaling, we hypothesize that the upregulation of endocannabinoids by thermogenic stimuli reported here constitutes a local autocrine negative feedback control by endocannabinoids over ␤3-adrenoceptorinduced BAT activation and WAT browning, which could account, in part, for the previously demonstrated enhancement of thermogenesis and energy expenditure by CB1 receptor inverse agonists, both in animal models of obesity [21, 22] and in obese humans [31]

Summary

Introduction

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. 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 specific 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 profiling 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.

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