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

代谢基因 MTCH2/mtch-1 在脂质稳态、长寿和生育能力中的机制作用

• 批准号: 10650721
• 负责人: ANDERS M NAAR
• 金额: $ 33.9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650721
• 关键词: Acetyl-CoA C-Acetyltransferase; Adult; Affect; Animals; Apoptosis; Binding; Biochemical; Biological Models; Body Weight; Caenorhabditis elegans; Calories; Cardiovascular system; Caring; Cell Culture Techniques; Cell Nucleus; Cells; Co-Immunoprecipitations; Coenzyme A; Cultured Cells; Data; Development; Diet; Drug or chemical Tissue Distribution; ESR1 gene; Enoyl-CoA Hydratase; Environmental Risk Factor; Enzymes; Epidemic; Family; Fatty Acids; Fatty acid glycerol esters; Fertility; Financial Hardship; Food; General Population; Genes; Genetic; Genetic Epistasis; Heart Diseases; Height; Homeostasis; Hormone Receptor; Human; Individual; Infertility; Inflammation; Insulin; Intestines; Knock-out; Lead; Life; Link; Lipids; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Medical; Metabolic; Methods; Mitochondria; Modeling; Molecular; Mus; Muscle; Mutagenesis; Mutate; Mutation; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Envelope; Nuclear Hormone Receptors; Obesity; Obesity associated disease; Outer Mitochondrial Membrane; Pathway interactions; Phenotype; Physiological; Play; Point Mutation; Predisposition; Prevalence; Process; Proliferating; Proteins; Public Health; Regulation; Reporting; Reproduction; Role; Signal Transduction; Signaling Molecule; Site; Skin; Stearoyl-CoA Desaturase; Sterility; System; Techniques; Testing; Thinness; Tissues; Visualization; cancer type; comorbidity; dietary restriction; dosage; experimental study; gene environment interaction; genome wide association study; germline stem cells; insight; knock-down; knockout gene; lipid metabolism; member; metabolic phenotype; model organism; mutant; obese person; overexpression; overweight adults; response; sedentary lifestyle; synergism

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.

超过70％的美国成年人超重，三分之一以上肥胖。这会导致肥胖合并症的患病率增加，例如II型糖尿病，心脏病和某些类型的癌症。许多环境因素，例如久坐的生活方式和高卡路里饮食有助于这种流行病。但是，在这些条件下发展肥胖的个体的倾向具有很强的遗传成分。大量基因组关联研究发现，特定基因，肥胖和肥胖相关疾病之间存在显着关联。通过了解导致肥胖症的基因环境相互作用，开发方法和疗法以降低肥胖水平和/或相关的合并症将更容易，这将增加公共健康并减轻与额外医疗相关的经济负担。在此应用中，我们深入研究了MTCH2的作用机理（线粒体载体2），这是最强的肥胖相关基因之一。在我们在几种模型系统（细胞，蠕虫和小鼠）中的初步研究中，我们发现激活该基因足以诱导肥胖，同时击倒该基因可显着降低肥胖性，这表明MTCH2既需要且足以足以使脂质积累。除了储能外，脂肪酸及其衍生物还可以用作信号分子。由于MTCH2会影响脂肪酸加工酶，因此脂质的组成可能会发生变化，因此它们的信号传导函数可能会发生变化，这可能是某些MTCH2表型的原因。我们将通过使用MTCH2突变或过表达的培养细胞和动物中的生化和质谱方法评估脂质的组成来研究这种可能性。除了调节脂肪含量外，我们还表明该基因会影响生育能力和寿命。但是，MTCH2调节所有三个过程的机制仍然难以捉摸。发现MTCH2主要驻留在线粒体外膜上，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（ESR1）功能。我们假设MTCH2可能会使激素受体置于线粒体以改变线粒体功能，或者成为线粒体 - 核核膜接触位点的一部分。这些MTCH2函数可能负责观察到的代谢表型。我们将在细胞，蠕虫和小鼠中使用深度定位，共定位和相互作用研究，以研究MTCH2所在的位置（细胞内和组织分布），其其他与其他蛋白结合的蛋白质以及哪些组织对于MTCH2调节肥胖，生育力和寿命至关重要。最后，我们将使用秀丽隐杆线虫遗传学（无菌性抑制筛查和可用点突变的分析）来发现介导MTCH2对脂质稳态，生育和寿命影响的途径和特定基因。