Nuclear Repressors in Genomic Control of Healthful Obesity

 描述（由申请人提供）：长期以来，人们已经认识到，中心（内脏）肥胖与不良代谢健康（包括胰岛素抵抗）相关，而外周（皮下）体脂是健康的或良性的，这一区别被认为是心脏代谢疾病伴肥胖的性二态风险的基础。然而，控制这些功能不同的仓库的起源和生理学的分子决定因素定义不清。使用条件遗传工程，我们已经确定了一个令人惊讶的作用，B细胞淋巴瘤6（BCL 6）的转录抑制在特定的脂肪组织编程库。我们发现BCL 6与关键的脂肪细胞转录调节因子PPARγ、C/EBP和EBF 1共定位，通过分化的脂肪细胞中的顺式调节位点控制代谢基因调控网络。因此，子宫内BCL 6的脂肪细胞特异性损失导致皮下脂肪组织而非内脏脂肪组织的自发和选择性扩张，从而将BCL 6鉴定为性二态性肥胖和分布的新的关键调节因子。在此，我们建议解剖BCL 6与核受体和激素信号传导途径的基因组整合，以确定其作为脂肪组织分布和功能的关键调节剂的作用，使用全面的细胞和分子，基因组和生理学方法，通过正常血糖-高胰岛素钳夹，脂肪因子产生和脂质代谢，以胰岛素敏感性为终点。鉴于不同的脂肪组织库产生胰岛素抵抗和心脏代谢疾病的不同风险，我们对BCL 6的研究将揭示新的治疗途径，以减少肥胖症，包括2型糖尿病（DM 2）的发病率。

 DESCRIPTION (provided by applicant): 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) transcriptional repressor in depot-specific adipose tissue programming. We find that BCL6 co-localizes with key adipocytic transcriptional regulators PPARγ, C/EBP, and EBF1 to control a metabolic gene regulatory network through cis-regulatory sites in differentiated adipocytes. Consequently, adipocyte-specific loss of BCL6 in utero results in spontaneous and selective expansion of subcutaneous, but not visceral, adipose tissue, identifying BCL6 as a new key regulator of sexually dimorphic obesity and distribution. 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 of BCL6 will reveal new therapeutic pathways to reduce the morbidity of obesity including type 2 diabetes mellitus (DM2).