Functional Interactions of SRC-2 and COUP-TFII in Muscle Energy Metabolism

代谢综合征是现代社会的主要健康危害。这些综合征，包括肥胖症， 糖尿病、肾功能障碍、神经病和心血管疾病已达到流行病的程度 在美国在上一个资助期，我们发现小鼠COUP-TFII等位基因的缺失 增加能量消耗并保护杂合小鼠免于高脂肪饮食诱导的肥胖， 提示COUP-TFII在调节能量稳态中起关键作用。SRC-2无效突变小鼠 表现出与COUP-TFII杂合子小鼠相似的能量代谢表型。我们的初步结果 显示过表达SRC-2小鼠在心肌中将燃料使用从脂质转换为碳水化合物 在骨骼肌特异性SRC-2基因敲除小鼠中也显示了脂质的失调，这表明SRC 2在心肌和骨骼肌的脂质代谢中起作用。有趣的是，过度表达COUP- 心肌中TFII表现出与SRC-2过表达小鼠相似的表型，这表明这两种TFII在心肌中的表达与SRC-2过表达小鼠相似。 这些因素在功能上相互作用以调节肌肉中的能量消耗。由于骨骼肌是一种 骨骼肌中的主要组织消耗能量和脂肪酸的低效使用是 胰岛素抵抗，我们将集中研究SRC-2和COUP-TFII在能量消耗中的作用， 骨骼特异性SRC-2和COUP-TFII过表达和低表达小鼠系。我们将首先确定 表型和关键分子的影响，这两个因素在调节能量消耗。到 了解潜在的机制，我们将确定直接下游靶基因和信号转导 SRC-2和COUP-TFII影响的途径，以使用微阵列和ChIP-seq控制能量代谢 分析.这些研究将增加我们对SRC-2和COUP-TFII如何共同调节的理解 细胞类型中的转录网络，在调节代谢途径中起关键作用， 体内能量平衡因此，本课题的研究具有重要的意义， 研究将为代谢紊乱治疗干预的未来发展提供新的见解。 相关性（参见说明）： 糖尿病及其相关代谢综合征的发病率上升是主要的健康危害， 现代社会能量消耗增加和对高脂饮食的抵抗导致肥胖 COUP-TFII和SRC-2突变小鼠所显示的结果表明，这两种因子是COUP-TFII和SRC-2突变小鼠的主要调节因子。 能量代谢了解COUP-TFII和SRC-2如何协同调节能量代谢 在肌肉中可能会导致及时发现新的治疗方法，为这些衰弱 疾病

Metabolic syndromes are major health hazards of the modern society. These syndromes, including obesity, diabetes, kidney dysfunction, neuropathy and cardiovascular diseases, have reached epidemic proportions in the United States. In the last funding period, we showed that loss of an allele of COUP-TFII in mice enhanced energy expenditure and protected the heterozygous mice from high fat diet induced obesity, suggesting that COUP-TFII plays a pivotal role in modulating energy homeostasis. SRC-2 null mutant mice exhibit similar energy metabolism phenotypes as COUP-TFII heterozygous mice. Our preliminary results show that mice over-expressing SRC-2 switch fuel usage from lipid to carbohydrate in cardiac muscle Dysregulation of lipids is also shown in skeletal muscle-specific SRC-2 knockout mice, suggesting that SRC 2 plays a role in lipid metabolism in cardiac and skeletal muscles. Intriguingly, mice overexpressing COUP- TFII in cardiac muscle exhibit similar phenotypes as SRC-2 overexpressing mice, implicating that these two factors functionally interact to regulate energy expenditure in the muscle. Since skeletal muscle is one of the major tissues dissipating energy and inefficient usage of fatty acids in the skeletal muscle is a hallmark of insulin resistance, we will focus our study on the role of SRC-2 and COUP-TFII in energy expenditure using skeletal specific SRC-2 and COUP-TFII over- and under- expression mouse lines. We will first determine the phenotypes and key molecules impacted by these two factors in the regulation of energy expenditure. To understand the underlying mechanisms, we will identify the direct downstream target genes and signaling pathways impacted by SRC-2 and COUP-TFII to control energy metabolism using microarray and ChlP-seq analysis. These studies will increase our understanding of how SRC-2 and COUP-TFII jointly regulate transcriptional networks in cell types that are pivotal in the regulation of metabolic pathways that govern energy homeostasis in vivo. Thus, our studies are highly significant and accomplishment of the proposed studies will provide new insights into future development of therapeutic interventions for metabolic disorders. RELEVANCE (See instructions): The rising incidence of diabetes and its associated metabolic syndromes are major health hazards for modern society. The enhanced energy expenditure and the resistance to high fat diet induced obesity exhibited by COUP-TFII and SRC-2 mutant mice suggest that these two factors are major regulators of energy metabolism. Understanding how COUP-TFII and SRC-2 act in concert to regulate energy metabolism in the muscle are likely to lead to the timely discovery of new treatment approaches for these debilitating diseases.