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）： 现代世界在肥胖症中经历了巨大的增长，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。甚至在5-10％的范围内，甚至适度的体重减轻也被证明可以防止肥胖的长期后果。不幸的是，当前的肥胖症治疗方案在其应用和效果方面仍然有限。 我们的初步数据表明，在生理工作负载下，肌肉ATP ATP敏感的K+（KATP）通道限制了肌肉能量消耗，而KATP渠道赤字会激发肌肉性能的额外能量成本。 KATP通道缺陷肌肉中效率低下的燃料代谢可减少体内脂肪沉积物促进瘦表型。当前的提案建立在这一发现的基础上，以确定KATP通道功能影响骨骼肌肉表现和身体能量平衡的机制。 我们假设由于生理工作量限制了KATP通道引起的膜电位调节，钙和钠向内电流，因此与离子稳态相关的能量消耗以及持续收缩。在剩余卡路里摄入条件下，这会促进体重增加。 KATP通道功能的破坏会导致细胞钙的加重，从而导致依赖性钙调蛋白激酶的能量消耗增加和蛋白激酶B（AKT）的激活。 AKT的这种胰岛素独立的磷酸化触发了先前未认识的肌肉信号传导级联反应，可以将增加活动相关的能量消耗转化为脂肪组织动员。该建议将直接研究（1）与活动相关能耗的KATP通道控制的分子机制； （2）随之而来的脂肪组织动员和体重减轻的机制以及（3）是否可以达到对骨骼肌肉KATP通道功能的干扰或下游信号级联，同时最大程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 - 对细胞和分离器官水平的生化和电生理研究将用于验证分子机制，以在整个体内获得的发现。了解这些机制将为有针对性的管理和预防肥胖和相关疾病以及未来的转化研究提供新的途径。 公共卫生相关性： 肥胖和超重对退伍军人健康和VA医疗保健系统造成了特别负担。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％的人超重或肥胖（31）。此外，在VHA人群中，与肥胖相关的疾病，例如高血压，糖尿病，缺血性心脏病，关节炎和癌症也很普遍（31）。在退伍军人中，超重和肥胖症的高度流行促使人们在体重控制方面的特殊努力，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传导机制来解决体重调节的机制。建立这些机制将揭示潜在的新目标，以预防肥胖和相关疾病。