Nuclear Repressors in Genomic Control of Healthful Obesity

 描述(申请人提供)：长期以来，人们一直认为中心性(内脏)肥胖与包括胰岛素抵抗在内的不良代谢健康有关，但外周(皮下)体脂是健康的或良性的，这一区别被认为是肥胖导致心脏代谢性疾病的性二相风险的基础。然而，控制这些功能截然不同的仓库的起源和生理的分子决定因素还没有得到很好的定义。利用条件基因工程，我们已经确定了B细胞淋巴瘤6(BCL6)转录抑制因子在仓库特异性脂肪组织编程中的惊人作用。我们发现bcl6与关键的脂肪细胞转录调控因子PPARγ、C/EBP和EBF1共定位，通过分化脂肪细胞中的顺式调控位点控制代谢基因调控网络。因此，BCL6在子宫中的脂肪细胞特异性丢失导致皮下脂肪组织的自发和选择性扩张，而不是内脏脂肪组织的自发和选择性扩张，从而确定BCL6是性二型肥胖和分布的新的关键调节因子。在这里，我们建议剖析BCL6与核受体和激素信号通路的基因组整合，以确定其作为脂肪组织分布和功能的关键调节因子的作用，采用综合的细胞和分子、基因组和生理方法，通过正常血糖-高胰岛素钳夹、脂肪因子的产生和脂代谢来调节胰岛素敏感性的终点。鉴于不同的脂肪组织对胰岛素抵抗和心脏代谢性疾病的不同风险，我们对BCL6的研究将揭示新的治疗途径，以降低包括2型糖尿病(DM2)在内的肥胖症的发病率。

 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).