Work

Brd2 disruption in mice causes severe obesity without Type 2 diabetes

Year: 2009

Type: article

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 wholebody disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory 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 beta-cells, where it normally inhibits beta-cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-alpha (tumour necrosis factor-alpha)-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.

Source: Biochemical Journal

DOI: 10.1042/bj20090928

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

Institution: Boston University

Language: English

Topic: Adipokines, Inflammation, and Metabolic Diseases

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases