Loss of Transcriptional Repression by Adipocyte BCL6 Results in Adiposity and Insulin Sensitivity

Senagolage, Madhavi Dushyanthi

doi:https://doi.org/10.21985/n2-maf1-9x26

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Loss of Transcriptional Repression by Adipocyte BCL6 Results in Adiposity and Insulin Sensitivity

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The epidemic of obesity and associated metabolic diseases have led to increased scrutiny of adipose tissue and its primary cell type, the adipocyte. However, studies show that regional adipose tissue distribution rather than obesity per se is a major determinant of metabolic disease risk. Despite having an obese body mass index, some individuals are considered “metabolically healthy” due to their normal intrahepatic fat content and insulin sensitivity. Compared to metabolically unhealthy obese counterparts, who have more centrally-distributed visceral and ectopic fat, metabolically healthy obese individuals possess increased gluteofemoral or lower-body subcutaneous fat. The molecular determinants governing body-fat distribution, depot-specific expansion and resulting metabolic impact remain poorly understood. Studies presented in my dissertation describe a novel role for transcription factor, B cell lymphoma 6 (BCL6), in the expansion of adipose tissue and regulation of glucose homeostasis. In adipocyte-specific knockout mice (Bcl6AKO), Bcl6 deletion results in strikingly increased inguinal subcutaneous tissue mass and adipocyte size. Despite exhibiting more pronounced high fat diet-induced adipose tissue inflammation, Bcl6AKO mice are protected from hepatic steatosis and exhibit remarkably enhanced whole body insulin sensitivity. Further, Bcl6AKO mice have increased serum levels of adiponectin and fatty acid esters of hydroxy fatty acids, which correlate with higher insulin sensitivity. Using deuterium label incorporation, we discovered that ablation of adipocyte Bcl6 enhances subcutaneous adipose tissue lipogenesis. Integrated genome-wide RNA expression and DNA binding analyses revealed that BCL6 controls gene networks involved in cell growth and fatty acid biosynthesis. Thus, our studies identify BCL6 as a regulator of adipose tissue expansion, inflammation, and whole-body insulin sensitivity.

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