Skeletal muscle KATP channels determine bodily energy balance

骨骼肌 KATP 通道决定身体能量平衡

• 批准号: 8293719
• 负责人: Leonid Zingman
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-25 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293719
• 关键词: Acute; Address; Adipose tissue; Affect; Area; Atrial Natriuretic Factor; Biochemical; Biology; Body Weight; Body Weight decreased; Body fat; Calcium; Calcium/calmodulin-dependent protein kinase; Cardiovascular Diseases; Consumption; Data; Deposition; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Epidemic; Equilibrium; Equipment; Fatty acid glycerol esters; Food Energy; Functional disorder; Goals; Growth; Homeostasis; Incidence; Intake; Investigation; Ions; Laboratories; Lipolysis; Malignant Neoplasms; Medical; Membrane; Membrane Potentials; Messenger RNA; Metabolism; Methods; Modeling; Molecular; Mus; Muscle; Muscle Cells; Obesity; Obesity associated disease; Organ; Peptide Signal Sequences; Peptides; Performance; Phenotype; Physiological; Population; Prevention; Production; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Role; Signal Transduction; Skeletal Muscle; Social Impacts; Sodium; Therapeutic; Transgenic Mice; Translating; Translations; Weight Gain; Weight maintenance regimen; Workload; base; biochemical model; calmodulin-dependent protein kinase II; cost; economic impact; energy balance; experience; inhibitor/antagonist; mortality; mouse model; novel; obesity treatment; prevent; response; success

DESCRIPTION (provided by applicant): The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect. Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and adipose tissue mobilization. We hypothesize that membrane potential modulation, due to KATP channel opening in response to a physiological workload, limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Conversely, disruption of KATP channel function would result in exaggerated cellular calcium turnover, causing increased energy consumption and activation of calcium/calmodulin dependent protein kinase (Ca2+/CaMKII). We propose, that induction of CaMKII triggers both Akt-dependent production and Ca2+- dependent secretion of a signaling peptide - musclin. This peptide is known for its ability to modulate clearance of atrial natriuretic peptide (ANP) - a potet activator of lipolysis. In this way, musclin signaling could translate increased activity related energy consumption into adipose tissue mobilization. The goal of this project is to directly study the molecular mechanism of KATP channel control of activity- related energy consumption and the mechanism of consequent adipose tissue mobilization and body weight reduction. The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related diseases. PUBLIC HEALTH RELEVANCE: Obesity is occurring at epidemic rates and has exceeded 30% of the U.S. population. Yet despite the medical, social and economic impact of obesity, only a few therapeutic options with limited success rates are currently available. This application addresses the novel hypotheses that metabolism-sensing KATP channels are important regulators of bodily energy balance and weight management, due to the effect of their function on muscle energy efficiency and mobilization of fat, and are potential targets for prevention and treatment of obesity.

描述（由申请人提供）：现代世界经历了肥胖的巨大增长，这是一种与糖尿病、心血管疾病和癌症的发病率和死亡率增加有关的疾病。即使是5-10%的适度减肥也被证明可以预防肥胖的长期后果。不幸的是，目前肥胖的治疗选择在应用和效果上仍然有限。我们的初步数据表明，肌层atp敏感K+ (KATP)通道限制了生理负荷下肌肉的能量消耗，而KATP通道缺陷会引起肌肉表现的额外能量消耗。缺乏KATP通道的肌肉中低效的燃料代谢减少了体脂沉积，促进了瘦表型。目前的建议建立在这一发现的基础上，以确定KATP通道功能影响骨骼肌性能和脂肪组织动员的机制。我们假设，由于KATP通道在生理负荷下打开，膜电位调节限制了钙和钠向内电流，从而限制了与离子稳态和收缩持续相关的能量消耗。在热量摄入过剩的情况下，这会促进体重增加。相反，KATP通道功能的破坏会导致细胞钙转换过度，导致能量消耗增加和钙/钙调素依赖性蛋白激酶（Ca2+/CaMKII）的激活。我们提出，CaMKII的诱导触发了akt依赖性的产生和Ca2+依赖性的信号肽-肌素的分泌。这种肽以其调节心房利钠肽（ANP）清除的能力而闻名，ANP是脂肪分解的潜在激活剂。通过这种方式，肌肉蛋白信号可以将活动相关的能量消耗增加转化为脂肪组织动员。本项目旨在直接研究KATP通道控制活动相关能量消耗的分子机制，以及由此引起的脂肪组织动员和体重减轻的机制。拟议的研究将跨多个模型进行-细胞和分离器官水平的生化和电生理研究将用于验证分子