Skeletal muscle ATP-sensitive potassium channels determine bodily energy balance

骨骼肌 ATP 敏感钾通道决定身体能量平衡

• 批准号: 8138795
• 负责人: Leonid Zingman
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138795
• 关键词: ATP sensitive potassium channel complex; Address; Adipose tissue; Adverse effects; Affect; Area; Arthritis; Atrial Natriuretic Factor; Biochemical; Biology; Body Weight; Body Weight decreased; Body fat; Boxing; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Cardiovascular Diseases; Consumption; Data; Deposition; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Equilibrium; Exercise Tolerance; Fatty acid glycerol esters; Food Energy; Functional disorder; Future; Growth; Health; Healthcare; Healthcare Systems; High Prevalence; Homeostasis; Hypertension; Incidence; Injection of therapeutic agent; Insulin; Intake; Investigation; Ions; Life Style; Link; Lipolysis; Malignant Neoplasms; Membrane; Membrane Potentials; Messenger RNA; Metabolism; Modeling; Molecular; Muscle; Myocardial Ischemia; Nuclear; Obesity; Obesity associated disease; Organ; Overweight; Peptide Signal Sequences; Peptides; Performance; Phenotype; Phosphorylation; Physical Endurance; Physiological; Population; Prevention; Production; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Resources; Serum; Signal Transduction; Skeletal Muscle; Sodium; Translating; Translational Research; Veterans; Weight Gain; Weight maintenance regimen; Workload; biochemical model; cost; energy balance; experience; improved; inhibitor/antagonist; mortality; novel; obesity prevention; prevent; response; stress tolerance

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 bodily energy balance. We hypothesize that membrane potential modulation due to KATP channel opening in response to 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. Disruption of KATP channel function results in aggravated cellular calcium turnover, causing increased energy consumption and activation of protein kinase B (Akt) by calcium dependent calmodulin kinase. This insulin independent phosphorylation of Akt triggers a previously unrecognized muscle signaling cascade which could translate increased activity related energy consumption into adipose tissue mobilization. This proposal will directly study (1) the molecular mechanism of KATP channel control of activity-related energy consumption; (2) the mechanism of consequent adipose tissue mobilization and body weight reduction and (3) whether interference with skeletal muscle KATP channel function or downstream signaling cascades can be achieved while minimizing side-effects and disruption of muscle performance. 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 disease and future translational research. PUBLIC HEALTH RELEVANCE: Obesity and overweight pose special burdens on veterans' health and the VA healthcare system. According to a recent study, 72% of veterans who use the VHA for health care are overweight or obese (31). Furthermore, obesity-associated conditions, such as hypertension, diabetes, ischemic heart disease, arthritis, and cancer are also highly prevalent in the VHA population (31). This high prevalence of overweight and obesity among veterans motivates special efforts at weight control to improve our veterans' health and lifestyles. The proposed study will address a mechanism of body weight regulation through understanding of ATP-sensitive potassium channel function in skeletal muscle, and signaling mechanisms linking muscle energy demand to mobilization of fat. Establishment of these mechanisms will reveal potential new targets for management and prevention of obesity and related diseases.

描述（由申请人提供）： 现代世界的肥胖症人数急剧增加，这种疾病与糖尿病、心血管疾病和癌症的发病率和死亡率增加有关。即使是 5-10% 范围内的适度减肥也已被证明可以预防肥胖的长期后果。不幸的是，目前肥胖症的治疗方案在应用和效果方面仍然有限。 我们的初步数据表明，肌膜 ATP 敏感 K+ (KATP) 通道限制生理负荷下的肌肉能量消耗，而 KATP 通道不足会引发肌肉表现的额外能量成本。 KATP 通道缺陷肌肉中燃料代谢效率低下，会减少体内脂肪沉积，从而促进瘦身表型。当前的提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身体能量平衡的机制。 我们假设，由于响应生理负荷而打开 KATP 通道而导致的膜电位调节限制了钙和钠的内向电流，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。 KATP 通道功能的破坏会导致细胞钙周转加剧，从而导致能量消耗增加以及钙依赖性钙调蛋白激酶激活蛋白激酶 B (Akt)。 Akt 的这种不依赖于胰岛素的磷酸化会触发以前未被识别的肌肉信号级联，这可能会将增加的活动相关能量消耗转化为脂肪组织动员。该提案将直接研究（1）KATP通道控制活动相关能量消耗的分子机制； （2）随后的脂肪组织动员和体重减轻的机制，以及（3）是否可以干扰骨骼肌 KATP 通道功能或下游信号级联，同时最大限度地减少副作用和肌肉性能的破坏。 拟议的研究将在多个模型中进行——对细胞和离体器官水平的生化和电生理学研究将用于验证在全身水平上获得的结果的分子机制。了解这些机制将为肥胖及相关疾病的针对性管理和预防以及未来的转化研究提供新途径。 公共卫生相关性： 肥胖和超重给退伍军人的健康和退伍军人管理局的医疗保健系统带来了特殊的负担。根据最近的一项研究，使用 VHA 进行医疗保健的退伍军人中有 72% 超重或肥胖 (31)。此外，与肥胖相关的疾病，如高血压、糖尿病、缺血性心脏病、关节炎和癌症在 VHA 人群中也非常普遍 (31)。退伍军人中超重和肥胖的高患病率促使人们在体重控制方面做出特别努力，以改善退伍军人的健康和生活方式。拟议的研究将通过了解骨骼肌中 ATP 敏感的钾通道功能以及将肌肉能量需求与脂肪动员联系起来的信号机制来解决体重调节机制。这些机制的建立将为肥胖及相关疾病的管理和预防揭示潜在的新目标。