The mechanistic role of metabolic gene MTCH2/mtch-1 in lipid homeostasis, longevity, and fertility

超过70%的美国成年人超重，超过三分之一的人肥胖。这导致肥胖合并症的患病率惊人地增加，例如II型糖尿病，心脏病和某些类型的癌症。许多环境因素，如久坐不动的生活方式和高热量饮食有助于这种流行病;然而，在这些条件下个体发展肥胖的倾向具有很强的遗传成分。大量的全基因组关联研究已经发现特定基因、肥胖和肥胖相关疾病之间存在显著关联。通过了解导致肥胖的基因-环境相互作用，将更容易开发降低肥胖水平和/或相关合并症的方法和疗法，这将提高公众健康水平并减少与额外医疗护理相关的经济负担。在本申请中，我们建议深入研究MTCH 2（线粒体载体2）的作用机制，MTCH 2是最强的肥胖相关基因之一。在我们对几种模型系统（细胞、蠕虫和小鼠）的初步研究中，我们发现激活该基因足以诱导肥胖，而敲除该基因可显著降低肥胖，这表明MTCH 2是脂质积累所必需的，也是足够的。除了能量储存之外，脂肪酸及其衍生物还可以作为信号分子。由于MTCH 2影响脂肪酸加工酶，因此脂质的组成及其信号功能可能发生变化，这可能是某些MTCH 2表型的原因。我们将通过使用生物化学和质谱方法在MTCH 2突变或过表达的培养细胞和动物中评估脂质的组成来研究这种可能性。除了调节脂肪含量外，我们还发现该基因影响生育力和寿命;然而，MTCH 2调节所有三个过程的机制仍然难以捉摸。MTCH 2被发现主要存在于线粒体外膜上，我们的初步数据表明它相互作用并可能影响雌激素受体1（ESR 1）的功能。我们假设MTCH 2可能将激素受体隔离到线粒体以改变线粒体功能，或者成为线粒体-ER-核膜接触位点的一部分。这些MTCH 2功能可能是观察到的代谢表型的原因。我们将在细胞，蠕虫和小鼠中进行深入的定位，共定位和相互作用研究，以研究MTCH 2的位置（细胞内和组织分布），它与哪些其他蛋白质结合，以及哪些组织对MTCH 2调节肥胖，生育力和寿命至关重要。最后，我们将使用C。elegans遗传学（不育抑制筛选和可用点突变的分析），以发现介导MTCH 2对脂质稳态，生育力和寿命影响的途径和特定基因。

Over 70% of US adults are overweight and over one-third are obese. This causes an alarming increase in the prevalence of obesity co-morbidities, such as type II diabetes, heart diseases, and certain types of cancer. Many environmental factors, such as a sedentary lifestyle and high calorie diets contribute to this epidemic; however, the predisposition of individuals to develop obesity under these conditions has a strong genetic component. Numerous Genome-Wide Association Studies have found significant associations between specific genes, obesity, and obesity associated diseases. By understanding gene-environment interactions that lead to obesity, it will be easier to develop approaches and therapies to reduce obesity levels and/or associated co-morbidities, which will increase the general public health and reduce financial burden associated with extra medical care. In this application, we propose in depth studies of the mechanism of action of MTCH2 (mitochondrial carrier 2), one of the strongest obesity-associated genes. In our preliminary studies in several model systems (cells, worms, and mice), we discovered that activating this gene is sufficient to induce obesity, while knocking down this gene significantly reduces adiposity indicating that MTCH2 is both required and sufficient for lipid accumulation. In addition to energy storage, fatty acids and their derivatives can serve as signaling molecules. Since MTCH2 influences fatty acid processing enzymes, it is possible that composition of lipids and therefore their signaling functions change, which might be the reason for some of the MTCH2 phenotypes. We will investigate this possibility by assessing the composition of lipids using biochemical and mass spectrometry approaches in cultured cells and animals with MTCH2 mutated or overexpressed. In addition to regulation of fat content, we showed that this gene influences fertility and longevity; however, the mechanisms by which MTCH2 regulates all three processes remain elusive. MTCH2 was found to be residing mainly on the outer mitochondrial membrane, and our preliminary data suggest that it interacts and could affect estrogen receptor 1 (ESR1) function. We hypothesize that MTCH2 might sequester hormone receptors to the mitochondria to alter mitochondrial function, or to be part of mitochondria-ER-nuclear membrane contact sites. It is possible that these MTCH2 functions are responsible for the observed metabolic phenotypes. We will use in depth localization, co-localization, and interaction studies in cells, worms, and mice to investigate where MTCH2 is located (intracellularly and tissue distribution), what other proteins it binds to, and which tissues are critical for MTCH2 regulation of adiposity, fertility and longevity. Finally, we will use C. elegans genetics (sterility suppressor screen and analysis of available point mutations) to discover the pathways and specific genes that mediate MTCH2 impact on lipid homeostasis, fertility, and lifespan.