Mechanistic Target of Rapamycin Pathways in Metabolism and Energy Expenditure

雷帕霉素代谢和能量消耗途径的机制目标

基本信息

批准号：
8881160
负责人：
David A Guertin
金额：
$ 41.04万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881160
关键词：
Adipocytes Adipose tissue Adult Anti-Obesity Agents Bioenergetics Biology Body mass index Brown Fat Burn injury Cardiovascular Diseases Cell Line Cells Complex Data Development Disease Dyslipidemias Energy Metabolism Epidemic Exhibits Fatty acid glycerol esters Genetically Engineered Mouse Glucose Goals Growth Health Healthcare Systems Homeostasis Human Individual Insulin Knock-out Lipids Lipomatosis Malignant Neoplasms Medicine Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Muscle Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Obesity PTEN gene Pathway interactions Phosphotransferases Pilot Projects Prevalence Property Proto-Oncogene Proteins c-akt Publishing Regulation Risk Factors Rodent Signal Transduction Sirolimus System Tamoxifen Testing Therapeutic Therapeutic Intervention Thermogenesis Tissues United States Weight Work aged base cell type cellular targeting deprivation energy balance glucose uptake in vivo inhibitor/antagonist interdisciplinary approach interest lipid biosynthesis mouse model novel research study targeted treatment

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the mechanisms that regulate cellular energy balance. Here, we are focusing on energy regulation in adipose tissue with a weighted focus on brown fat. Interest in brown fat bioenergetics is rapidly gaining momentum because of the recent realization that adult humans possess a significant quantity of brown fat or brown fat-like cells that may exhibit metabolically favorable "fat burning" properties. It is speculated that therapeutically increasing brown fat energy expenditure could defend against obesity. Importantly however, very little is known about the molecular signals that control energy expenditure in adipose tissue, or brown fat differentiation and function. The objective of this proposal is to test the hypothesis that the mechanistic target of rapamycin complex 2 (mTORC2) is a critical regulator of metabolism and energy expenditure in brown fat. To test this, we are taking a multidisciplinary approach utilizing genetically engineered mice, primary cell lines, and pharmacological agents to study the mechanisms by which mTORC2 and its substrates regulate energy balance in adipose tissue. Our work is yielding very interesting and unexpected preliminary findings that suggest inhibiting mTORC2 reprograms cellular metabolism and may increase brown fat activity. In Specific Aim 1, we elucidate the mechanism by which mTORC2 reprograms metabolism. In Specific Aim 2, we test the in vivo relevance of our hypothesis and our preliminary findings using novel mouse models. In Specific Aim 3, we ask if pharmacologically inhibiting mTORC2 can treat pathological fat accumulation. Elucidating the metabolic regulatory circuits under mTORC2 control in brown fat will have important implications in advancing therapies targeting cellular bioenergetics.