The Gq signalling pathway inhibits brown and beige adipose tissue.

Katarina Klepac,Anja Glöde,Evi Kostenis,Sven Enerbäck,Andrea Wilderman,Matthias J Betz,Matthias Blüher,Thorsten Gnad,Martin E Lidell,Loren M Brown,Marc Freichel,Aileen Balkow,Ana Kilić,Beate Herrmann,Jürgen Wess,Katharina Simon,Paul A Insel,Alexander Pfeifer,Gabi König

doi:10.1038/ncomms10895

Abstract

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity.

Highlights

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults
Class A receptors increased from 139 to 188 receptors, whereas 13 out of the 20 adhesion G protein-coupled receptors (GPCRs) expressed in preadipocytes decreased upon differentiation with five of them decreasing below the detection limit (Table 1)
With respect to coupling to heterotrimeric G proteins, we found that 14.0 and 31.5% of the GPCRs detected in brown adipocytes (BAs) interact with Gs and Gi, respectively (Fig. 1b)

Summary

Introduction

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. We profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). G protein-coupled receptors (GPCRs) are a large family of seven transmembrane proteins[11,12] that regulate important biological processes in diverse tissues including adipose tissue[13,14]. The analysis of BAT GPCRs has focused mainly on a few Gs-coupled receptors (for example, b-adrenergic[4] and adenosine[18] receptors) that activate cAMP signalling and UCP1-dependent thermogenesis. Using pharmacological and genetic approaches, we found that Gq, via modulation of RhoA signalling, regulates adipogenesis of BAs in vitro and in vivo

Methods

Results

Conclusion