Molecular regulation of skeletal muscle thermogenesis

摘要 肥胖的诱因是能量储存相对于能量消耗的增加，直到 一个新的能量平衡建立在较高的病理生理重量。肥胖症正在以惊人的速度增长 在美国，大约三分之一的成年人和五分之一的儿童被归类为肥胖。此外, 在直接的医疗费用、失业和病态方面，肥胖是导致胰岛素抵抗的主要因素 和2型糖尿病。在过去的十年里，在实验层面上，已经集中了大量的努力 通过棕色/米色脂肪组织的发育/激活来增加能量消耗 生热作用。与脂肪组织相比，骨骼肌总共约占50% 体重是基础代谢率的主要决定因素，也是能量增加的主要驱动力 在体力活动中发生的支出。此外，不自主的骨骼肌收缩或 寒冷时，基于自主活动的骨骼肌收缩是产生热量的主要原因 诱导生热，可达到静息基础代谢率的15-20倍。 在我们对TIGAR基因敲除小鼠的表型鉴定过程中，令我们惊讶的是，这些小鼠表现出 显著的抗寒表型，独立于棕色和米色脂肪细胞的功能，是 骨骼肌产热增加。我们计划利用小鼠遗传学、新陈代谢图谱和 确定TIGAR引起的抗寒性的分子基础的生理评估 缺乏症。我们目前发现的具体新奇方面是：i)TIGAR缺乏不会影响 室温下的能量产生但显著增强了冷诱导的生热作用，II)增加了 生热反应是由于骨骼肌ATP周转通过增加而直接激活的 收缩活动和iii)骨骼肌收缩活动增加是由于TIGAR缺乏所致 神经肌肉连接处的胆碱能神经元。机构示意图(S) TIGAR基因敲除小鼠的耐寒机制如图1所示。 拟议研究计划的新方面是：1)从基因上确定TIGAR缺乏症 通过增加胆碱能张力来增强基于骨骼肌收缩的产热，2) 确定骨骼肌产热的增强激活是否是由于 TIGAR蛋白依赖的结合作用(S)和/或由于TIGAR磷酸酶活性丧失，3) 要绘制在温度中和温度之间发生的代谢流量的结果变化，房间 骨骼肌的温度和冷暴露，以及4)鉴定新的TIGAR依赖 胆碱能神经元信号增加的分子途径。

Abstract The induction of obesity results from an increase in energy storage relative to energy expenditure and until a new energy equilibrium is established at higher pathophysiologic weight. Obesity is increasing at an alarming rate in the USA with approximately one-third of adults and one-fifth of children classified as obese. In addition, to the direct health care costs, work loss and morbidly, obesity is the primary factor driving insulin resistance and type 2 diabetes. At the experimental level over the past decade there has been a substantial effort focused on increasing energy expenditure through the development/activation of brown/beige adipose tissue thermogenesis. In contrast to adipose tissue, collectively skeletal muscle accounts for approximately 50% of body mass, is the primary determinant of basal metabolic rate and is the major driver of increased energy expenditure that occurs during physical activity. In addition, involuntary skeletal muscle contractions or voluntary activity based skeletal muscle contractions accounts for the majority of heat production during cold induced thermogenesis that can reach 15-20 times the resting basal metabolic rate. During our phenotypic characterization of the TIGAR knockout mice, to our surprise these mice display a remarkable cold resistant phenotype that is independent of brown and beige adipocyte function and is a result of increased skeletal muscle thermogenesis. We plan to use mouse genetics, metabolic profiling and physiologic assessments to determine the molecular basis for the cold resistance that occurs due to TIGAR deficiency. The specific novel aspects of our current findings are that: i) TIGAR deficiency does not affect energy production at room temperature but markedly enhances cold induced thermogenesis, ii) the increased thermogenic response is due to a direct activation of skeletal muscle ATP turnover through increased contractile activity and iii) the increased skeletal muscle contractile activity results from TIGAR deficiency in cholinergic neurons at the neuromuscular junction. A schematic representation of the mechanism(s) responsible for cold resistance in TIGAR knockout mice is illustrated and described in Figure 1. The specific novel aspects of the proposed research plan are: 1) to genetically determine whether TIGAR deficiency enhances skeletal muscle contraction based thermogenesis through increased cholinergic tone, 2) to determine whether the enhanced activation of skeletal muscle thermogenesis results from a loss of TIGAR protein dependent binding interaction(s) and/or due to a loss of TIGAR phosphatase activity, 3) to map the resultant changes in metabolic flux that occurs between thermoneutrality, room temperature and cold exposure in skeletal muscle, and 4) to identify the novel TIGAR-dependent molecular pathway responsible for the increase in cholinergic neuron signaling.