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The Role of Adipocyte Lipolysis in Thermoregulation

脂肪细胞脂解作用在体温调节中的作用

基本信息

批准号：
10225316
负责人：
Liqing Yu
金额：
$ 43.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225316
关键词：
ATP Synthesis Pathway Adipocytes Adipose tissue Adrenergic Receptor Adult Affect Biochemical Blood Brown Fat Capsid Proteins Cells Coupling Cytosol Denervation Diabetes Mellitus Diet Disease Endocrine Energy Metabolism Fasting Fatty Liver Fatty acid glycerol esters Food Future Gene Expression Generations Genes Glucose Homeostasis Hormones Hydrolysis Knock-out Knockout Mice Lipase Lipids Lipolysis Mammals Measures Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Morbidity - disease rate Mus Names Nonesterified Fatty Acids Norepinephrine Nutritional Obesity Obesity Epidemic Outcome Overnutrition Pathway interactions Pharmacology Physiologic Thermoregulation Play Population Process Proteins Respiration Role Series Starvation Sympathetic Nervous System Systems Biology Temperature Testing Thermogenesis Thick Time Tissues Tracer Triglycerides Tyrosine 3-Monooxygenase adipokines base comparative energy balance experimental study genetic manipulation glucose disposal in vivo in vivo evaluation inhibitor innovation insight insulin sensitivity lipid metabolism mortality nerve supply novel novel strategies perilipin recruit subcutaneous therapeutic target uncoupling protein 1 uptake

项目摘要

Project Summary Adipose tissue critically regulates whole-body energy homeostasis. Mammals have two major adipose tissues: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores excess energy while BAT dissipates energy as heat for non-shivering thermogenesis. Some adipocytes in WAT, like brown adipocytes, express uncoupling protein-1 (UCP1), a protein that mediates heat generation by un-coupling mitochondrial respiration from ATP synthesis. This population of adipocytes is recently named “beige” or “brite” adipocytes. The quantity of beige adipocytes increases during cold adaptation or sympathetic activation, a process referred to as WAT browning. Mobilization of stored cellular energy for use during starvation or increased energy demand (e.g., cold adaptation) requires hydrolysis of triglycerides stored in cytosolic lipid droplets (LDs) (i.e., intracellular lipolysis). A gene critically implicated in intracellular lipolysis is CGI-58 (Comparative Gene Identification-58). In mammals, CGI-58 is ubiquitously expressed with the highest expression in fat. It interacts with LD coat proteins and activates ATGL (Adipose Triglyceride Lipase) to promote intracellular lipolysis. It was believed that intracellular lipolysis in BAT is essential for thermogenesis, but this has not been examined in vivo. We surprisingly found that mice lacking CGI-58 in BAT, i.e., BAT-specific CGI-58 knockout (BAT-KO) mice, are not cold sensitive even in the fasted state. This proposal is to define the underlying adaptive mechanisms. Our preliminary studies suggest a central hypothesis: BAT deficiency in intracellular lipolysis may reprogram BAT to take up more circulating thermogenic substrates derived from WAT lipolysis and diet and by inducing WAT thermogenesis through activation of the sympathetic nervous system. We will test this hypothesis by examining BAT thermogenesis, BAT uptake of circulating substrates, and WAT thermogenesis under different temperature, sympathetic, and nutritional states. We will also explore the origin of beige adipocytes in BAT-KO mice. Additionally, we will examine whether WAT lipolysis is required for thermogenesis and WAT browning in BAT-KO mice by using a pharmacological inhibitor of intracellular lipolysis and by simultaneous deletion of CGI-58 in both BAT and WAT (FAT-KO mice). In some experiments, we will compare adipose CGI-58 and ATGL KO mice to gain insights into other lipolytic roles of CGI-58. Furthermore, we will define how BAT lipolysis regulates energy balance, glucose disposal, insulin sensitivity, and tissue lipid metabolism. Finally, we will search for novel insights into how lipolysis deficiency augments adipose sympathetic drive. We will generally measure blood levels of lipids/adipokines/hormones, and tissue levels of lipids/gene expression to establish how CGI-58 deficiency in different adipocytes regulates lipid/energy metabolism at biochemical and molecular levels. Thermogenesis dissipates energy. Perturbation of energy balance is a hallmark of common metabolic disorders, which contribute substantially to disease morbidity and mortality. Findings from our studies hold promise of revealing novel approaches for control of overnutrition-induced metabolic disease.

项目总结