Regulation of Energy Metabolism and Life Span in Mammals through Indy and its

能源平衡和预期寿命之间存在着密切的相关性。Indy(=我还没有死)基因的表达减少，它编码了三元和二元酸的细胞表面转运体，延长了寿命，并以类似于热量限制的方式增强了线粒体的生物合成。最初建议的基础是我们观察到哺乳动物Indy同源物(Slc13A5，Mindy)的缺失也在功能和转录水平上诱导了类似热量限制的状态，并且Mindy-KO小鼠的特征是线粒体生物合成增加，肝脏脂质氧化，以及新生脂肪生成减少。这些代谢变化保护Mindy-KO小鼠免受营养引起的肥胖和胰岛素抵抗的影响。在这项提案的第一个资助期内，我们在黑腹小鼠先前工作的基础上，开始了对Mindy-KO小鼠的长寿和衰老研究。我们第一次观察到Mindy-KO小鼠似乎比发育迟缓的对照组小鼠的寿命和健康时间明显延长，并且Mindy-KO小鼠的寿命和健康时间与卡路里限制的小鼠相似，尽管Mindy-KO小鼠没有减少食物摄入量。同样，我们观察到，在人类和非人类灵长类动物中，Mindy的低表达伴随着消瘦和代谢健康，而在肥胖的胰岛素抵抗合并脂肪肝的患者中，Mindy的表达更高，这一效应是通过白细胞介素6介导的。我们进一步证明，在HepG2和HEK293细胞中提高Mindy水平可以增强柠檬酸盐的脂肪生成，并诱导特定的表观遗传蛋白修饰，这在代谢调节和衰老中是重要的。随着这一建议的扩展，我们现在将研究有助于改善Mindy-KO小鼠健康寿命和衰老的分子和细胞机制，重点是表观遗传机制。此外，我们将使用我们在第一个资助期建立的功能损失和获得模型，更详细地研究Mindy在肝脏中的功能。这些模型将在脂肪和葡萄糖代谢以及衰老方面进行测试。总之，我们的研究将对衰老和寿命调节的病理生理学及其与代谢性疾病的关系产生新的见解，并进一步验证Mindy作为治疗与饮食和衰老相关的代谢性疾病的目标，如非酒精性脂肪性肝病和胰岛素抵抗。

A close correlation exists between energy balance and life expectancy. Reduced expression of the Indy (= I am not dead yet) gene, which encodes a cell surface transporter for tri- and dicarboxylic acids, prolongs life span and augments mitochondrial biogenesis in a manner akin to caloric restriction in D. melanogaster and C. elegans. The basis of the initial proposal was our observation that deletion of the mammalian Indy homolog (Slc13A5, mIndy) in mice also induced a caloric restriction-like state, on the functional and on the transcriptional level and that mINDY-KO mice were characterized by increased mitochondrial biogenesis, hepatic lipid oxidation, and reduced de novo lipogenesis. These metabolic changes protected mINDY-KO mice from nutritionally induced adiposity and insulin resistance. Within the first funding period of this proposal, we started longevity and ageing studies in mINDY-KO mice on the basis of previous work in D. melanogaster. We observed for the first time that mINDY-KO mice seem to have markedly extended life- and health spans compared to littermate control mice, and that life- and health span in mINDY-KO mice is similar to those of calorically restricted mice, although mINDY-KO mice did not reduce food intake. In the same vein, we observed that lower mIndy expression in humans and non-human primates goes along with leanness and metabolic health, while higher mIndy expression is found in obese insulin resistant patients with fatty liver, an effect mediated via interleukin-6. We went on to show that raising mIndy levels in HepG2 and HEK293 cells enhances lipogenesis from citrate, and induces specific epigenetic protein modifications, which are important in metabolic regulation and ageing. With the extension of this proposal, we will now study the molecular and cellular mechanisms contributing to the improvement in health span and ageing in mINDY-KO mice with a focus on epigenetic mechanisms. Moreover, we will study the function of mIndy in more detail in the liver, using loss and gain of function models that we generated during the first funding period. These models will be tested in regard to lipid and glucose metabolism and ageing. Together, our studies will generate new insight into the pathophysiology of ageing and life span regulation, its relation to metabolic disease and to validate mIndy further as a target for the treatment of diet and aging related metabolic diseases, such as non-alcoholic fatty liver disease and insulin resistance.