Resistance to diet-induced obesity and improved insulin sensitivity in mice with a regulator of g protein signaling-insensitive G184S Gnai2 allele

OBJECTIVE-Guanine nucleotide binding protein (G protein)mediated signaling plays major roles in endocrine/metabolic function. Regulators of G protein signaling (RGSs, or RGS proteins) are responsible for the subsecond turn off of G protein signaling and are inhibitors of signal transduction in vitro, but the physiological function of RGS proteins remains poorly defined in part because of functional redundancy. RESEARCH DESIGN AND METHODS-We explore the role of RGS proteins and G alpha(i2) in the physiologic regulation of body weight and glucose homeostasis by studying genomic knock-in mice expressing RGS-insensitive G alpha(i2) with a G184S mutation that blocks RGS protein binding and GTPase acceleration. RESULTS-Homozygous G alpha(G184S)(i2) knock-in mice show slightly reduced adiposity. On a high-fat diet, male G alpha(G184S)(i2) mice are resistant to weight gain, have decreased body fat, and are protected from insulin resistance. This appears to be a result of increased energy expenditure. Both male and female G alpha(G184S)(i2) mice on a high-fat diet also exhibit enhanced insulin sensitivity and increased glucose tolerance despite females having similar weight gain and adiposity compared with wild-type female mice. CONCLUSIONS-RGS proteins and G alpha(i2), signaling play important roles in the control of insulin sensitivity and glucose metabolism. Identification of the specific RGS proteins involved might permit their consideration as potential therapeutic targets for obesity-related insulin resistance and type 2 diabetes.