It has long been recognized that central (visceral) obesity is associated with adverse metabolic health including insulin resistance, yet peripheral (subcutaneous) body fat is healthful or benign, a distinction believed to underlie the sexually dimorphic risk of cardiometabolic disease with obesity. However, the molecular determinants that control the origins and physiology of these functionally distinct depots are poorly defined. Using conditional genetic engineering, we have identified a surprising role for the B cell lymphoma 6 (BCL6) repressor in depot-specific adipose tissue programming. We find that BCL6 co-localizes with PPARg, C/EBP, and EBF1 to control a metabolic gene regulatory network through cis-regulatory sites in differentiated adipocytes, and that adipocyte-specific loss of BCL6 in utero results in spontaneous and selective expansion of subcutaneous, but not visceral, adipose tissue. Herein, we propose to dissect the genomic integration of BCL6 with nuclear receptor and hormonal signaling pathways to determine its role as a key regulator of adipose tissue distribution and function, using comprehensive cell and molecular, genomic, and physiologic approaches with endpoints of insulin sensitivity by euglycemic-hyperinsulinemic clamp, adipokine production, and lipid metabolism. Given that distinct adipose tissue depots exert differential risk of insulin resistance and cardiometabolic disease, our studies may reveal BCL6 as a new therapeutic target for type 2 diabetes mellitus.
|Effective start/end date||5/10/16 → 3/31/21|
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK108987-05)