Brd2 disruption in mice causes severe obesity without Type 2 diabetes

Fangnian Wang, Hongsheng Liu, Wanda P. Blanton, Anna Belkina, Nathan K LeBrasseur, Gerald V. Denis

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that whole-body disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated proinflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic β-cells, where it normally inhibits β-cellmitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ (peroxisome-proliferator-activated receptor-γ) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-α (tumour necrosis factor-α)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.

Original languageEnglish (US)
Pages (from-to)71-83
Number of pages13
JournalBiochemical Journal
Volume425
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Fingerprint

Brown Adipose Tissue
Glucose Intolerance
Morbid Obesity
Medical problems
Adipocytes
Type 2 Diabetes Mellitus
Insulin Resistance
Insulin
Tissue
Weights and Measures
Glucose
Co-Repressor Proteins
Adipogenesis
White Adipose Tissue
Peroxisome Proliferator-Activated Receptors
Metabolome
Thermogenesis
Adiponectin
Hyperinsulinism
Genes

Keywords

  • β-cell
  • Adipogenesis
  • Brd2
  • Bromodomain
  • Energy balance
  • Obesity
  • Type 2 diabetes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Brd2 disruption in mice causes severe obesity without Type 2 diabetes. / Wang, Fangnian; Liu, Hongsheng; Blanton, Wanda P.; Belkina, Anna; LeBrasseur, Nathan K; Denis, Gerald V.

In: Biochemical Journal, Vol. 425, No. 1, 01.01.2010, p. 71-83.

Research output: Contribution to journalArticle

Wang, F, Liu, H, Blanton, WP, Belkina, A, LeBrasseur, NK & Denis, GV 2010, 'Brd2 disruption in mice causes severe obesity without Type 2 diabetes', Biochemical Journal, vol. 425, no. 1, pp. 71-83. https://doi.org/10.1042/BJ20090928
Wang, Fangnian ; Liu, Hongsheng ; Blanton, Wanda P. ; Belkina, Anna ; LeBrasseur, Nathan K ; Denis, Gerald V. / Brd2 disruption in mice causes severe obesity without Type 2 diabetes. In: Biochemical Journal. 2010 ; Vol. 425, No. 1. pp. 71-83.
@article{0ab6e86014874d2fbc98577ac03b832c,
title = "Brd2 disruption in mice causes severe obesity without Type 2 diabetes",
abstract = "Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that whole-body disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated proinflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic β-cells, where it normally inhibits β-cellmitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ (peroxisome-proliferator-activated receptor-γ) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-α (tumour necrosis factor-α)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.",
keywords = "β-cell, Adipogenesis, Brd2, Bromodomain, Energy balance, Obesity, Type 2 diabetes",
author = "Fangnian Wang and Hongsheng Liu and Blanton, {Wanda P.} and Anna Belkina and LeBrasseur, {Nathan K} and Denis, {Gerald V.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1042/BJ20090928",
language = "English (US)",
volume = "425",
pages = "71--83",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "1",

}

TY - JOUR

T1 - Brd2 disruption in mice causes severe obesity without Type 2 diabetes

AU - Wang, Fangnian

AU - Liu, Hongsheng

AU - Blanton, Wanda P.

AU - Belkina, Anna

AU - LeBrasseur, Nathan K

AU - Denis, Gerald V.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that whole-body disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated proinflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic β-cells, where it normally inhibits β-cellmitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ (peroxisome-proliferator-activated receptor-γ) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-α (tumour necrosis factor-α)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.

AB - Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that whole-body disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated proinflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic β-cells, where it normally inhibits β-cellmitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ (peroxisome-proliferator-activated receptor-γ) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-α (tumour necrosis factor-α)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.

KW - β-cell

KW - Adipogenesis

KW - Brd2

KW - Bromodomain

KW - Energy balance

KW - Obesity

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=72449150767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72449150767&partnerID=8YFLogxK

U2 - 10.1042/BJ20090928

DO - 10.1042/BJ20090928

M3 - Article

VL - 425

SP - 71

EP - 83

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 1

ER -