Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes

Abstract

Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity-induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from insulin resistance, glucose intolerance and pancreatic beta cell dysfunction, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible, innovative target to treat obesity and diabetes through modulation of the function of a chromatin code reader.

Figure 1. Reduced expression of Brd2 potentiates insulin transcription in embryonic stem cells

(A) Schematic of mouse insulin 1 promoter that drives expression of eGFP (eGFP). Promoter elements are also shown: bovine growth hormone poly A sequence (bGH-PA) and hygromycin resistance (Hgr^r). (B) Visual (vis) and fluorescence (Ins-GFP) micrographs of ES cells transfected with the construct in (A) and permitted to undergo differentiation. Undifferentiated cells were cultured on gelatin-coated tissue culture plastic in the presence of Leukemia Inhibitory Factor (LIF) (undifferentiated), then LIF was withdrawn to permit the formation of embryoid bodies for two weeks (embryoid bodies), and culture was continued for an additional two weeks to permit additional differentiation (differentiated). Magnification is shown at the right hand edge of the Figure. The parental ES cells (E14 parental; w/w) were compared to Brd2 KO ES cells (RRE050; w/lo) as described in Wang et al 2009, at the same stage of differentiation.