Abstract 19265: Adipose Tissue Overexpression of a Constitutively Active Isoform of Chrebp Protects Against Obesity and Insulin Resistance in Mice

Abstract

Obesity is associated with increased risk for T2DM and CVD in humans, and nutrients typically consumed in excess in the Western diet, such as various saturated fats, cholesterol, and simple sugars, are thought to regulate the activity of metabolic genes that modulate risk for obesity and insulin resistance. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to regulate hepatic intracellular glucose and lipid homeostasis independent of the effects of insulin. Recent publications have reported that white adipose tissue (WAT) and brown adipose tissue (BAT) depots also highly express ChREBP, that ChREBP expression is upregulated during adipocyte differentiation, and that increased ChREBP activation in adipocytes is associated with obesity, but not insulin resistance, in the context of adipose tissue-specific GLUT4 overexpression in mice. However, independent modulation of ChREBP expression in adipose tissue has not yet been achieved. To better understand the impact of adipocyte-specific ChREBP activity on intracellular and whole-body metabolism, we have generated a novel transgenic mouse model that overexpresses a constitutively active ChREBP (caChREBP) isoform in adipose tissue (ap2-Cre;eGFPflox-caChREBP mice). When fed either standard chow diet or Western-type diet (WD) for 10 weeks, total fat mass, but not lean mass, was significantly decreased in male ap2-Cre;eGFPflox-caChREBP mice versus ap2-Cre littermate controls. Both glucose tolerance testing and insulin tolerance testing revealed no differences between groups of chow-fed mice, but significantly improved insulin sensitivity in WD-fed male ap2-Cre;eGFPflox-caChREBP mice. RER during the daily active cycle was increased in WD-fed ap2-Cre;eGFPflox-caChREBP mice, implying greater utilization of carbohydrate for energy expenditure. Transgenic overexpression of caChREBP resulted in increased expression of lipogenic genes, but not genes involved in adipocyte differentiation, in gonadal fat. Taken together, these data indicate that upregulation of ChREBP activity in adipose tissue may defend against WD-induced obesity and insulin resistance, despite increased adipocyte expression of lipogenic genes.