GNB3 overexpression causes obesity and metabolic syndrome.
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...
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doaj-6377138046d049ce892d693e550162442020-11-25T01:45:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011212e018876310.1371/journal.pone.0188763GNB3 overexpression causes obesity and metabolic syndrome.Alev Cagla OzdemirGrace M WynnAimee VesterM Neale WeitzmannGretchen N NeighShanthi SrinivasanM Katharine RuddThe 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.http://europepmc.org/articles/PMC5716578?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alev Cagla Ozdemir Grace M Wynn Aimee Vester M Neale Weitzmann Gretchen N Neigh Shanthi Srinivasan M Katharine Rudd |
spellingShingle |
Alev Cagla Ozdemir Grace M Wynn Aimee Vester M Neale Weitzmann Gretchen N Neigh Shanthi Srinivasan M Katharine Rudd GNB3 overexpression causes obesity and metabolic syndrome. PLoS ONE |
author_facet |
Alev Cagla Ozdemir Grace M Wynn Aimee Vester M Neale Weitzmann Gretchen N Neigh Shanthi Srinivasan M Katharine Rudd |
author_sort |
Alev Cagla Ozdemir |
title |
GNB3 overexpression causes obesity and metabolic syndrome. |
title_short |
GNB3 overexpression causes obesity and metabolic syndrome. |
title_full |
GNB3 overexpression causes obesity and metabolic syndrome. |
title_fullStr |
GNB3 overexpression causes obesity and metabolic syndrome. |
title_full_unstemmed |
GNB3 overexpression causes obesity and metabolic syndrome. |
title_sort |
gnb3 overexpression causes obesity and metabolic syndrome. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2017-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5716578?pdf=render |
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