Congratulations to Dr. Gerald V. Denis and his Cancer Research Center colleagues on the publication of their “Brd2 disruption in mice causes severe obesity without type 2 diabetes” in the 2 November 2009 issue of the Biochemical Journal (http://www.biochemj.org/bj/imps/abs/BJ20090928.htm).

Obesity has become a worldwide epidemic and an alarming public health concern, stemming from multifaceted causes that include genetic susceptibility, increased availability of high-energy foods and decreased physical activity in modern society. The wide-ranging, health-related impacts of obesity include diabetes mellitus, coronary heart disease, non-alcoholic fatty liver disease and some forms of cancer. We have made a surprising discovery that deficiency of a gene called Brd2 causes both extreme obesity in mice and simultaneously protects the mice from Type 2 diabetes. The mice end up weighing the human equivalent of 600 pounds, but fed a regular (not high-fat) diet of rodent chow. The mice eat only as they wish and are not force fed. 

The most medically significant and newsworthy aspect of this report is that these mice completely avoid glucose intolerance and Type 2 diabetes, despite their extreme obesity. A few patients seen in weight management clinics in the US can weighed as much as 1000 pounds before bariatric surgery, but some manage to avoid Type 2 diabetes despite their weight. We have insufficient understanding of why these individuals are protected. We propose that these mice may be of major significance to help us understand the approximately one-third of the adult obese population that also manages to avoid pancreatic beta cell failure; this avenue of research likely has important therapeutic implications for the obesity epidemic. 

Here is the abstract: 

Biochem. J. (2009) Immediate Publication, doi:10.1042/BJ20090928 

Brd2 disruption in mice causes severe obesity without type 2 diabetes

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

Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, U.S.A. gdenis@bu.edu 

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 previously reported on a novel, double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF-like functions that regulates chromatin. Here we show that whole-body disruption of Brd2, an unusual MHC gene, causes lifelong, severe obesity in mice with pancreatic islet expansion, hyperinsulinemia, 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 lower 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 cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-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.

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