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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：
9271966
负责人：
Grant D Barish
金额：
$ 33.93万
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/9271966
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 Hormonal 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 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 disorder risk epigenomics feeding genome-wide glucose production glucose uptake 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).