GNB3 overexpression leads to obesity in a mouse model Open Access

Ozdemir, Alev Cagla (Fall 2017)

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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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