GNB3 overexpression causes obesity and metabolic syndrome.

Alev Cagla Ozdemir,Gretchen N Neigh,Aimee Vester,M Katharine Rudd,Grace M Wynn,M Neale Weitzmann,Shanthi Srinivasan,Chi Bun Chan

doi:10.1371/journal.pone.0188763

Alev Cagla Ozdemir, Gretchen N Neigh + Show 6 more

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https://doi.org/10.1371/journal.pone.0188763

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Abstract

The G-protein beta subunit 3 (GNB3) gene has been implicated in obesity risk; however, the molecular mechanism of GNB3-related disease is unknown. GNB3 duplication is responsible for a syndromic form of childhood obesity, and an activating DNA sequence variant (C825T) in GNB3 is also associated with obesity. To test the hypothesis that GNB3 overexpression causes obesity, we created bacterial artificial chromosome (BAC) transgenic mice that carry an extra copy of the human GNB3 risk allele. Here we show that GNB3-T/+ mice have increased adiposity, but not greater food intake or a defect in satiety. GNB3-T/+ mice have elevated fasting plasma glucose, insulin, and C-peptide, as well as glucose intolerance, indicating type 2 diabetes. Fasting plasma leptin, triglycerides, cholesterol and phospholipids are elevated, suggesting metabolic syndrome. Based on a battery of behavioral tests, GNB3-T/+ mice did not exhibit anxiety- or depressive-like phenotypes. GNB3-T/+ and wild-type animals have similar activity levels and heat production; however, GNB3-T/+ mice exhibit dysregulation of acute thermogenesis. Finally, Ucp1 expression is significantly lower in white adipose tissue (WAT) in GNB3-T/+ mice, suggestive of WAT remodeling that could lead to impaired cellular thermogenesis. Taken together, our study provides the first functional link between GNB3 and obesity, and presents insight into novel pathways that could be applied to combat obesity and type 2 diabetes.

Highlights

Obesity is a chronic disease associated with significant morbidity and mortality, affecting over 600 million adults globally [1]
The bacterial artificial chromosome (BAC) transgenic G-protein beta subunit 3 (GNB3)-T/+ mice were developed on a FVB background as previously described [14]
We refer to mice heterozygous for the human BAC transgene as GNB3-T/+

Summary

Introduction

Obesity is a chronic disease associated with significant morbidity and mortality, affecting over 600 million adults globally [1]. Since the identification of leptin (LEP) as the first obesity gene [7], several other Mendelian forms of non-syndromic obesity have been discovered [8,9,10]. Along with monogenic forms of obesity, genetic disorders like Prader-Willi and Bardet-Biedl syndromes include obesity as a significant phenotype [9]. Genome-wide association studies have identified alleles that contribute to common forms of obesity [11]. Though many genetic causes have been discovered, additional genes are necessary to explain the “missing heritability” in obesity [12,13]

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