Molecular mechanisms of thermogenesis

产热的分子机制

• 批准号: 8109075
• 负责人: Edward M Mills
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109075
• 关键词: Adult; Amino Acid Motifs; Amphetamines; Animals; Anti-Obesity Agents; Behavior; Binding; Bioenergetics; Biology; Brown Fat; Catabolism; Collaborations; Complex; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Drug Delivery Systems; Enzymes; Essential Fatty Acids; Exercise; Exhibits; Fasting; Fatty Acids; Fatty acid glycerol esters; Fever; Fluorescence; Food; Foundations; Functional disorder; Goals; Grant; Health; Heating; Homologous Gene; Human; Immunoprecipitation; In Vitro; Individual; Inflammation; Insulin Resistance; Intervention; Link; Lipids; Lipopolysaccharides; Literature; Mammals; Mediating; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Matrix; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Mutagenesis; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nutrient; Obesity; Oleic Acids; Organ; Overnutrition; Oxidants; Oxidation-Reduction; Palmitates; Pathway interactions; Physiological; Physiology; Protein Binding; Proteins; Protons; Publications; Recombinant Proteins; Regulation; Relative (related person); Respiration; Rodent; Saturated Fatty Acids; Signal Transduction; Skeletal Muscle; Stimulus; Testing; Thermogenesis; Thyroid Hormones; Tissues; Toxic effect; Unsaturated Fats; Unsaturated Fatty Acids; Work; analog; arachidonate; base; delta(3,5),delta(2,4)-dienoyl-CoA isomerase; fatty acid metabolism; fatty acid transport; in vitro Assay; in vivo; mitochondrial dysfunction; mitochondrial uncoupling protein; mitochondrial uncoupling protein 3; muscle metabolism; novel; overexpression; oxidation; pi bond; protein activation; response; saturated fat; sedentary; wasting

DESCRIPTION (provided by applicant): Over the past few decades, the surge in the rates of obesity and type II diabetes in this nation has led to devastating health consequences. Stimulation of inducible mitochondrial thermogenesis, which wastes energy consumed as heat, is an attractive intervention strategy for obesity and related metabolic disorders. Uncoupling proteins (UCPs) are highly conserved thermogenic mediators that regulate inducible mitochondrial heat production in diverse tissues by controlling mitochondrial proton leak. In mammals, brown fat UCP1 is the established mediator of cold-induced thermogenesis. However, the low abundance of brown fat in a large percentage of adults challenges its thermoregulatory importance in these individuals and suggests that alternative thermogenic mechanisms exist. Skeletal muscle is also a key thermogenic organ in mammals, but whether UCPs are involved in muscle thermogenesis is unclear. We found that mice lacking the skeletal muscle-enriched UCP1 homolog UCP3 have sharply blunted (60- 100%) thermogenic responses to amphetamine-type stimulants, and the physiological fever inducers norepinephrine and lipopolysaccharide. In addition, mice specifically overexpressing UCP3 in muscle exhibit increased thermogenic responses. Fatty acids are essential activators of UCP1-3 induced proton leak, and therefore, thermogenesis. However, despite enormous efforts, the mechanistic basis for fatty acid activation of UCPs is unclear. Unsaturated, healthy fatty acids (e.g. oleate) are strong activators of UCPs relative to the more deleterious saturated analogs. Oleate and related fatty acids require auxiliary metabolic enzymes for full metabolism by beta oxidation. We found that UCP3 forms a novel, oleate- sensitive and functionally important interaction with 2,4, 3,5 dienoyl-CoA isomerase, a fatty acid metabolizing enzyme in the mitochondrial matrix whose substrates include many of the same fatty acids that bind and activate UCP3. Work in this grant will characterize the binding mechanisms and functional metabolic relevancy of this novel mitochondrial complex guided by three specific aims: Aim 1 - To define the structural and bioenergetic mechanisms regulating the binding of dienoyl-CoA isomerase and UCP3. Aim 2 - To establish the functional importance of dienoyl CoA isomerase for UCP3-induced mitochondrial uncoupling, and of UCP3 for the enzymatic activity of dienoyl CoA isomerase. Aim 3 - To explore the physiological functions of dienoyl CoA isomerase as a key regulator of lipid induced thermogenesis and fat catabolism in muscle and other UCP-relevant thermoregulatory tissues.

描述(申请人提供)：在过去的几十年里，肥胖率和II型糖尿病在这个国家的激增导致了毁灭性的健康后果。刺激可诱导的线粒体产热是治疗肥胖和相关代谢紊乱的一种有吸引力的干预策略。线粒体产热是一种浪费能量作为热量消耗的机制。解偶联蛋白(UCPs)是一种高度保守的生热介质，通过控制线粒体质子泄漏来调节不同组织中可诱导的线粒体产热。在哺乳动物中，棕色脂肪UCP1是冷诱导产热的既定中介。然而，在很大比例的成年人中，棕色脂肪的低丰度挑战了它对这些人体温调节的重要性，并表明存在替代的生热机制。骨骼肌也是哺乳动物的关键产热器官，但UCPs是否参与肌肉产热尚不清楚。我们发现，缺乏富含骨骼肌的UCP1同系物UCP3的小鼠对苯丙胺类兴奋剂和生理性发热诱导剂去甲肾上腺素和脂多糖的发热反应急剧减弱(60%-100%)。此外，在肌肉中特别过度表达UCP3的小鼠表现出更强的生热反应。脂肪酸是UCP1-3诱导的质子泄漏的必要激活剂，因此是生热作用。然而，尽管付出了巨大的努力，但脂肪酸激活UCPs的机制基础尚不清楚。与更有害的饱和类似物相比，不饱和、健康的脂肪酸(如油酸)是UCPs的强大激活剂。油酸和相关脂肪酸需要辅助代谢酶才能通过β氧化完全代谢。我们发现UCP3与2，4，3，5二烯酰辅酶A异构酶形成了一种新的油酸敏感的重要功能相互作用，2，4，3，5二烯酰辅酶A异构酶是线粒体基质中的一种脂肪酸代谢酶，其底物中含有许多与UCP3结合和激活的相同脂肪酸。这项赠款的工作将表征这种由三个特定目标指导的新型线粒体复合体的结合机制和功能代谢相关性：目标1-确定调节二烯酰辅酶A异构酶和UCP3结合的结构和生物能量机制。目的2-确定二烯酰辅酶A异构酶在UCP3诱导的线粒体解偶联中的功能重要性，以及UCP3对二烯酰辅酶A异构酶活性的作用。目的3-探讨二烯酰辅酶A异构酶作为脂肪诱导的产热和脂肪分解代谢的关键调节因子在肌肉和其他UCP相关的体温调节组织中的生理功能。