GNB3 overexpression leads to obesity in a mouse model Open Access
Ozdemir, Alev Cagla (Fall 2017)
Abstract
Obesity is a highly heritable disorder of excess accumulation of body fat. As a worldwide epidemic, obesity and its associated comorbidities such as type 2 diabetes, cardiovascular disease and cancer, impose major public health challenges. We described a genetic syndrome of obesity and intellectual disability in humans, where an unbalanced chromosomal translocation leads to an 8.5-Megabase (Mb) duplication of chromosome 12p and a 7.0-Mb deletion of chromosome 8p. One of the duplicated genes is GNB3, which encodes G protein β3. A cytosine to thymine (C825T) polymorphism in GNB3 is associated with hypertension, obesity and metabolic syndrome in genome-wide association studies; however, the mechanism of GNB3-related obesity is unknown. We created bacterial artificial chromosome (BAC) transgenic mice that carry an extra copy of the T risk allele of GNB3. GNB3-T/+ mice weighed significantly more than wild-types (WT) starting at age 6-7 week onwards. We show that GNB3-T/+ mice have increased adiposity, indicated by greater subcutaneous and visceral white adipose tissue (WAT) and brown adipose tissue (BAT) depots, larger white adipocytes, and larger livers compared to WT. Lean mass is approximately the same in GNB3-T/+ and WT mice, suggesting that the difference in weight is strictly due to an increase in fat mass. GNB3-T/+ mice have similar food intake, activity levels and heat production compared to WT. Strikingly, GNB3-T/+ mice have decreased Ucp1 expression and increased adipogenic marker expression in subcutaneous WAT, suggesting a conversion of subcutaneous WAT into a less UCP1+ and a less beige but whiter tissue. We also created BAC transgenic mice that have an extra copy of the non-risk C allele of GNB3 or the mouse ortholog of Gnb3. GNB3-C mice weigh less than WT, have proper glucose tolerance, and elevated blood lipid levels, suggesting that GNB3-C overexpression is protective of weight gain, but not of elevated blood lipids. On the other hand, mice with additional copies of Gnb3 weigh more and have greater adiposity than WT, depending on BAC copy number. Taken together, these data demonstrate that GNB3 alleles and expression levels impact body weight, and support a role for GNB3 overexpression in obesity.
Table of Contents
Chapter 1: General Introduction
1. Obesity 2
a. Obesity and statistics 2
b. Genetics of obesity 3
i. Obesity and genetic variation 3
ii. Heritability 3
1. Twin and adoption studies 4
2. Racial and ethnic differences 5
iii. Monogenic obesity 5
1. Leptin deficiency and leptin receptor mutations 6
2. Melanocortin 4 receptor (MC4R) mutations 7
3. POMC/Prohormone convertase 1 7
iv. Genetic obesity syndromes with developmental delay 8
1. Prader-Willi syndrome 8
2. Bardet-Biedl syndrome 8
3. Albright hereditary osteodystrophy 9
4. BDNF and TRKB deficiency 9
5. SIM1 deficiency 10
v. Genome-wide association studies 10
vi. Copy number variants and obesity 11
vii. Epigenetics of obesity 13
viii. Missing heritability in obesity 13
2. Adipose tissue 14
a. White adipose tissue 14
b. Brown adipose tissue 15
c. Tools to study adiposity 15
3. G proteins 17
a. Principles of G protein signaling 17
b. G protein β subunits 18
c. G protein β3 (GNB3) and the GNB3 C825T polymorphism 18
d. G proteins in obesity 20
e. GNB3 duplication in a childhood obesity syndrome 20
4. Dissertation goals 21
Chapter 2: Mouse model implicates GNB3 duplication in a childhood obesity syndrome
Abstract 28
Introduction 28
Results 30
Discussion 35
Materials and Methods 37
Chapter 3: GNB3 overexpression causes obesity and metabolic syndrome
Abstract 84
Introduction 84
Results 86
Discussion 91
Materials and Methods 95
Chapter 4: GNB3 alleles and expression levels dictate severity of obesity
Abstract 134
Introduction 134
Results 135
Discussion 142
Materials and Methods 145
Chapter 5: General conclusions and future directions
General conclusions 174
Future directions 181
References 189
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