RGS2: A multifunctional signaling hub that balances brown adipose tissue function and differentiation

Katarina Klepac, JuHee Yang, Staffan Hildebrand, Alexander Pfeifer


The most important regulators of brown adipose tissue (BAT) activity include members of the G protein-coupled receptors (GPCRs) that may signal via Gs, Gq or other G proteins. Regulators of G Protein Signaling (RGS) are important modulators of GPCR activity. Klepac and colleagues elucidated the role of RGS2 in brown adipocyte differentiation and BAT function. RGS2-deficient (RGS2-/-) brown adipocytes exhibited a severe defect in adipogenesis that was caused by increased Gq signaling. Analysis of RGS2-/- mice revealed an unexpected increase in lipolysis and BAT activity due to increased Gs signaling. Thus, RGS2 is a multifunctional inhibitor of Gq that also regulates Gs signaling in BAT.

Objective: Recruitment of brown adipose tissue (BAT) is a potential new strategy for increasing energy expenditure (EE) to treat obesity. G protein–coupled receptors (GPCRs) represent promising targets to activate BAT, as they are the major regulators of BAT biological function. To identify new regulators of GPCR signaling in BAT, we studied the role of Regulator of G protein Signaling 2 (RGS2) in brown adipocytes and BAT.

Methods: We combined pharmacological and genetic tools to investigate the role of RGS2 in BAT in vitro and in vivo. Adipocyte progenitors were isolated from wild-type (WT) and RGS2 knockout (RGS2−/−) BAT and differentiated to brown adipocytes. This approach was complemented with knockdown of RGS2 using lentiviral shRNAs (shRGS2). Adipogenesis was analyzed by Oil Red O staining and by determining the expression of adipogenic and thermogenic markers. Pharmacological modulators and fluorescence staining of F-acting stress fibers were employed to identify the underlying signaling pathways. In vivo, the activity of BAT was assessed by ex vivo lipolysis and by measuring whole-body EE by indirect calorimetry in metabolic cages.

Results: RGS2 is highly expressed in BAT, and treatment with cGMP—an important enhancer of brown adipocyte differentiation—further increased RGS2 expression. Loss of RGS2 strongly suppressed adipogenesis and the expression of thermogenic genes in brown adipocytes. Mechanistically, we found increased Gq/Rho/Rho kinase (ROCK) signaling in the absence of RGS2. Surprisingly, in vivo analysis revealed elevated BAT activity in RGS2-deficient mice that was caused by enhanced Gs/cAMP signaling.

Conclusion: Overall, RGS2 regulates two major signaling pathways in BAT: Gq and Gs. On the one hand, RGS2 promotes brown adipogenesis by counteracting the inhibitory action of Gq/Rho/ROCK signaling. On the other hand, RGS2 decreases the activity of BAT through the inhibition of Gs signaling and cAMP production. Thus, RGS2 might represent a stress modulator that protects BAT from overstimulation.