Nuclear Repressors in Genomic Control of Healthful Obesity

健康肥胖基因组控制中的核抑制因子

基本信息

批准号：
9455671
负责人：
Grant D Barish
金额：
$ 33.89万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-10 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9455671
关键词：
Ablation Address Adipocytes Adipose tissue Anatomy Animals BCL6 gene Benign Binding Body fat CCAAT-Enhancer-Binding Proteins Cells Central obesity ChIP-seq Closure by clamp Data Development Diet Disease Drug or chemical Tissue Distribution Energy Metabolism Epigenetic Process Exhibits Fatty acid glycerol esters Gene Targeting Genes Genetic Genetic Engineering Genetic Transcription Genomics Health Heart Diseases Hepatic High Fat Diet Histology Histones Hyperplasia Hypertrophy Immune Indirect Calorimetry Inflammation Insulin Resistance Isotopes Knockout Mice Lipids Lipolysis Magnetic Resonance Imaging Measurement Measures Mediating Metabolic Metabolic Diseases Metabolism Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear RNA Nuclear Receptors Obesity PPAR gamma Pathology Pathway interactions Peripheral Physiological Physiology Production Receptor Signaling Regulation Regulator Genes Repression Risk Role Signal Pathway Site Skin Somatotropin Switch Genes Testing Therapeutic Tissue Banks Tissue Expansion Tissues Transcription Repressor/Corepressor Transplantation Visceral X-Ray Computed Tomography adipocyte differentiation adipokines base blood glucose regulation cardiometabolic risk cardiometabolism epigenomics feeding genome-wide glucose production glucose uptake hormonal signals improved in utero in vivo insight insulin sensitivity lipid biosynthesis lipid metabolism male novel therapeutics prevent programs public health relevance response sexual dimorphism subcutaneous transcriptome sequencing

项目摘要

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).

描述（由适用提供）：长期以来，人们已经认识到，中枢（内脏）肥胖与不良代谢健康有关，包括胰岛素抵抗，但外周（皮下）体内脂肪是健康的或良性的，这是一种与肥胖症患心代谢性疾病的性二态风险的区别。但是，控制这些功能上不同沉积物的起源和生理的分子决定剂的定义很低。使用条件基因工程，我们确定了在沉积物特异性脂肪组织编程中B细胞淋巴瘤6（BCL6）转录反射器的惊人作用。我们发现BCL6与关键的脂肪细胞转录调节剂PPARγ，C/EBP和EBF1共定位，以通过分化脂肪细胞中的顺式调节位点来控制代谢基因调节网络。因此，子宫内Bcl6的脂肪细胞特异性损失导致皮下而不是内脏的脂肪组织的赞助和选择性扩展，从而将Bcl6鉴定为性二态肥胖和分布的新关键调节剂。 Herein, we propose to dissect the genomic integration of BCL6 with nuclear receiver and horseal 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.鉴于不同的脂肪组织沉积物具有胰岛素抵抗和心脏代谢疾病的差异风险，我们对BCL6的研究将揭示新的治疗途径，以降低肥胖症的发病率，包括2型糖尿病（DM2）。