Skeletal Muscle–Specific Activation of Gq Signaling Maintains Glucose Homeostasis

Abstract

Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Because G-protein–coupled receptors (GPCRs) represent excellent drug targets, we hypothesized that activation of specific functional classes of SKM GPCRs might lead to improved glucose homeostasis in type 2 diabetes. At present, little is known about the in vivo metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM Gq signaling can improve SKM glucose uptake and whole-body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a Gq-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM Gq signaling greatly promoted glucose uptake into SKM and significantly improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. In contrast, obese mutant mice that lacked both Gαq and Gα11 selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of Gq signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM Gq signaling may prove useful as novel antidiabetic drugs.

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

“…By contrast, obese mice lacking Gaq/11 in SKM showed impaired glucose homeostasis [35]. Bone et al [35] also demonstrated that activation of Gqcoupled oxytocin receptors enhances glucose uptake in primary human SKM cells (Fig. 3; Table 1).…”

“…Selective activation of this designer GPCR promoted glucose uptake into SKM and improved glucose homeostasis in diet-induced obese, glucose-intolerant mice [35]. By contrast, obese mice lacking Gaq/11 in SKM showed impaired glucose homeostasis [35]. Bone et al [35] also demonstrated that activation of Gqcoupled oxytocin receptors enhances glucose uptake in primary human SKM cells (Fig.…”

“…A recent in vivo study examined mice that expressed a Gq-linked designer GPCR (Gq DREADD) selectively in SKM [35]. Selective activation of this designer GPCR promoted glucose uptake into SKM and improved glucose homeostasis in diet-induced obese, glucose-intolerant mice [35]. By contrast, obese mice lacking Gaq/11 in SKM showed impaired glucose homeostasis [35].…”

“…Originally, beta-arrestins were identified as regulators of GPCR internalization and desensitization [22]; however, more recent studies have shown that beta-arrestins can also act as signaling molecules on their own, mediating G protein-independent signaling [23][24][25][26][27][28][29][30]. GPCRs modulate a very large number of metabolic functions including glucose production, glucose uptake, insulin action, insulin secretion, and differentiation and expansion of various cell types [5,[31][32][33][34][35][36][37]. Thus, it is not surprising that GPCRs have emerged as prime drug targets for the treatment of metabolic diseases such as obesity and T2D.…”

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

“…We recently reported that activation of Gq-coupled receptors enhanced AMPK-mediated glucose uptake in muscle [ 91 ]. Whether there is a synergistic effect between hepatic AMPK activation by metformin and Gq receptor activation in the muscle (and other tissues, including liver) is a subject to be examined.…”