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

Diabetes. 2008 Jan;57(1):77-85. doi: 10.2337/db07-0599. Epub 2007 Oct 10.

Abstract

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(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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / anatomy & histology
  • Amino Acid Substitution
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Crosses, Genetic
  • Diet*
  • Dietary Fats*
  • Energy Intake
  • Female
  • GTP-Binding Protein Regulators / physiology*
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics*
  • Glucose Tolerance Test
  • Immunity, Innate / genetics
  • Insulin / pharmacology*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / genetics*
  • Obesity / prevention & control
  • Oxygen Consumption
  • Signal Transduction / physiology
  • Triglycerides

Substances

  • Blood Glucose
  • Dietary Fats
  • GTP-Binding Protein Regulators
  • Insulin
  • Triglycerides
  • GTP-Binding Protein alpha Subunit, Gi2
  • Gnai2 protein, mouse