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: 8640933
• 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/8640933
• 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.

描述(申请人提供)：现代世界经历了肥胖的巨大增长，肥胖是一种与糖尿病、心血管疾病和癌症的发病率和死亡率增加相关的疾病。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，目前治疗肥胖症的选择在应用和效果方面仍然有限。我们的初步数据表明，在生理负荷下，肌膜上的ATP敏感性K+(KATP)通道限制了肌肉的能量消耗，而KATP通道的缺失会引起肌肉表现的额外能量成本。KATP通道缺陷肌肉的低效燃料代谢减少了体内脂肪沉积，促进了瘦肉型。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通道对生理负荷的开放，膜电位调制限制了钙和钠的内向电流，从而限制了与离子动态平衡和收缩持续相关的能量消耗。在卡路里摄入过剩的情况下，这会促进体重增加。相反，KATP通道功能的破坏会导致细胞钙周转过度，导致能量消耗增加，并激活钙/钙调蛋白依赖的蛋白激酶(Ca~(2+)/CaMKII)。我们认为，CaMKII的诱导既触发了Akt依赖的产生，也触发了钙依赖的信号肽-Musclin的分泌。这种多肽以其调节心钠素(ANP)清除的能力而闻名，心钠素(ANP)是一种POTET脂解激活剂。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。本项目的目标是直接研究KATP通道控制与活动相关的能量消耗的分子机制，以及随后脂肪组织动员和体重减轻的机制。拟议的研究将通过多个模型进行--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 在整个身体层面上获得结果的机制。了解这些机制将为肥胖和相关疾病的有针对性的管理和预防提供新的途径。