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Control of adipose function through a PRDM16/Type 1 Interferon Axis

通过 PRDM16/1 型干扰素轴控制脂肪功能

基本信息

批准号：
9706410
负责人：
Patrick Seale
金额：
$ 7.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2016-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9706410
关键词：
Adipocytes Adipose tissue Animals Automobile Driving Binding Bioenergetics Biological Assay Biology Brown Fat Cell Culture Techniques Cell Respiration Cessation of life Chromatin Chronic Disease Complex DNA Binding Deposition Depressed mood Development Distress FAT gene Fatty acid glycerol esters Genes Genetic Models Genetic Transcription Glucose Goals Heart Diseases High Fat Diet Histones Human IFNAR1 gene IRF1 gene Immune Insulin Resistance Interferon Activation Interferon Receptor Interferons Knock-out Link Lipids Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolism Methods Methylation Mitochondria Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Pathway interactions Physiological Play Public Health Reporter Genes Role Signal Transduction Skeletal Muscle System Testing Tissues Toxic Actions Virus Diseases Weight Gain Work Zinc Fingers adipocyte differentiation cell type chromatin immunoprecipitation feeding genome editing in vivo loss of function mitochondrial dysfunction mutant neutralizing antibody novel overexpression premature prevent programs promoter recruit response transcription factor

项目摘要

Summary Obesity is a leading cause of chronic illness and premature death in the U.S. A promising avenue to reduce obesity and associated diseases is through increasing the activity of energy-burning brown and beige adipocytes. In addition to promoting fat loss, brown fat cells have the capacity to consume large amounts of lipid and glucose and thereby reduce their toxic actions in many tissues. PRDM16, a zinc-finger transcription factor plays a critical role in regulating brown and beige adipocyte differentiation. We recently discovered that, in addition to driving a brown fat-selective gene program, PRDM16 powerfully suppresses transcriptional responses to innate immune type 1 Interferon (IFN) signaling in adipose cells and tissues. Moreover, we found that Type 1 IFN signaling, which is primarily associated with viral infection, is elevated in adipose tissues by high fat diet and that type 1 IFN activation represses mitochondrial function in adipocytes. These exciting findings led us to hypothesize that PRDM16-mediated suppression of Type 1 IFN-signaling preserves the thermogenic function of brown fat under normal physiological conditions. However, we speculate that persistent increases in type 1 IFN signaling caused by high fat diet leads to mitochondrial dysfunction in brown fat and, in doing so, contributes significantly to the development of systemic metabolic disease. In this project, we will investigate the mechanisms by which PRDM16 blocks the IFN-response in adipose cells and determine the role of type 1 IFN in driving high fat diet-induced weight gain and systemic insulin resistance. In aim 1, we will determine the mechanism by which PRDM16 is recruited to IFN-responsive genes and study how PRDM16 functions in chromatin to repress the transcription of these genes. In aim 2, we will use cell culture and in vivo genetic models to examine the interaction between PRDM16 and type 1 IFN-signaling in regulating brown fat function. In Aim 3, we will determine if blocking high fat diet-linked type 1 IFN-responses in adipose could be used to reduce metabolic disease. Altogether, these studies will define a novel role for PRDM16 and type 1 IFN signaling in regulating adipose biology and systemic metabolism.

总结