Skeletal muscle KATP channels determine bodily energy balance

骨骼肌 KATP 通道决定身体能量平衡

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：现代世界肥胖症的发病率急剧上升，肥胖症是一种与糖尿病、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% 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脂肪组织动员的机制。我们假设，由于 KATP 通道响应生理负荷而打开，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。相反，KATP 通道功能的破坏会导致细胞钙周转过度，导致能量消耗增加和钙/钙调蛋白依赖性蛋白激酶 (Ca2+/CaMKII) 的激活。我们认为，CaMKII 的诱导会触发信号肽 - 肌肉蛋白的 Akt 依赖性产生和 Ca2+ 依赖性分泌。这种肽因其调节心房钠尿肽 (ANP)（一种有效的脂肪分解激活剂）的清除能力而闻名。通过这种方式，肌肉蛋白信号传导可以将增加的活动相关能量消耗转化为脂肪组织动员。该项目的目标是直接研究KATP通道控制活动相关能量消耗的分子机制以及随后的脂肪组织动员和体重减轻的机制。拟议的研究将在多个模型中进行——细胞和离体器官水平的生化和电生理学研究将用于验证分子水平在全身水平上获得的发现的机制。了解这些机制将为有针对性地管理和预防肥胖及相关疾病提供新途径。