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: 8244931
• 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/8244931
• 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.

描述（由申请人提供）：