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.


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.
Huang
Xinyan
X
Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, USA.
Charbeneau
Raelene A
RA
Fu
Ying
Y
Kaur
Kuljeet
K
Gerin
Isabelle
I
MacDougald
Ormond A
OA
Neubig
Richard R
RR
D000273:Adipose Tissue / Q000033:anatomy & histology; D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003433:Crosses, Genetic; D004032:Diet; D004041:Dietary Fats; D002149:Energy Intake; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000502:physiology*; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics*; D005951:Glucose Tolerance Test; D007113:Immunity, Innate / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D010101:Oxygen Consumption; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides
D001786:Blood Glucose; D004041:Dietary Fats; D020555:GTP-Binding Protein Regulators; D007328:Insulin; D014280:Triglycerides; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse