Resistance to Diet-Induced Obesity and Improved Insulin Sensitivity in Mice With a Regulator of G Protein Signaling–Insensitive G184S Gnai2 Allele

Abstract

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. 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. Homozygous G alpha(i2)(G184S) knock-in mice show slightly reduced adiposity. On a high-fat diet, male G alpha(i2)(G184S) 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(i2)(G184S) 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. 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.