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

Abstract

ObjectiveRecruitment 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.MethodsWe 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.ResultsRGS2 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.ConclusionOverall, 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.

Emerging Roles for Regulator of G Protein Signaling 2 in (Patho)physiology

“…In addition, recruitment of inflammatory cells, neutrophils and eosinophils to the bronchoalveolar lavage fluid were significantly increased in RGS2 -/mice (George et al, 2017). Altogether, these data suggest that RGS2 plays a protective against airway hyperreactivity and may be a promising Additional suggested physiological functions for RGS2 include, but are not limited to, kidney fibrosis progression regulation (Jang et al, 2014), brown adipose tissue function and differentiation (Klepac et al, 2019), as well as serving as a key regulator of pancreatic β-cell function (Dong et al, 2017). In a 2017 study, RGS2 -/mice were found to have enhanced β-cell apoptosis and dysregulated insulin secretion in response to glucose challenge.…”

The Increased Expression of Regulator of G-Protein Signaling 2 (RGS2) Inhibits Insulin-Induced Akt Phosphorylation and Is Associated with Uncontrolled Glycemia in Patients with Type 2 Diabetes

“…Regulator of G-protein signaling (RGS) proteins terminate G-protein signaling by accelerating GTPase activity of heterotrimeric Gα-subunits [ 7 ]. RGS2 is one of the most widely studied proteins of the RGS family and preferentially inhibits signaling mediated by heterotrimeric G q/11 proteins [ 8 , 9 ] and has been associated with critical physiological processes such as regulation of blood pressure, cardiac remodeling, and immune responses [ 10 ]. As a critical regulator of G protein-coupled receptor (GPCR) signaling, its deficiency or low expression under experimental or pathological conditions severely affects important physiological conditions.…”

“…As a critical regulator of G protein-coupled receptor (GPCR) signaling, its deficiency or low expression under experimental or pathological conditions severely affects important physiological conditions. RGS2 deficiency, for example, accelerates the progression of kidney fibrosis [ 11 ], enhances β-cell apoptosis and dysregulate insulin secretion in response to a glucose challenge [ 12 ], and promotes severe adipogenesis and lipolysis in brown adipose tissue [ 9 ]. Additionally, RGS2 upregulation attenuates phenylephrine hypertrophic effects via α 1 -adrenergic receptors in cultured ventricular myocytes [ 13 ].…”

Morphological and biological properties of silica nanoparticles for CRTC3-siRNA delivery and downregulation of the RGS2 expression in preadipocytes

“…12 The pathway by which CRTC3 protein may be mediating lipolysis has not been described in detail, but evidence suggests that it is through activation of RGS2 expression. 6,13 In order to evaluate the effective approach to downregulate RGS2 gene expression mediated by CRTC3-siRNA in human adipocytes, the aims of this study were to synthesize SiO 2 NPs, to characterize their morphological properties, to evaluate their cytotoxicity effect, and to assess their intracellular localization and capability to deliver siRNA to cultured cells to downregulate RGS2 gene expression. This study evaluates the potential that SiO 2 NPs conjugated with CRTC3-siRNA have to function as a delivery vehicle in an in vitro model to downregulate RGS2 expression levels in HPAd.…”