缺氧诱导的线粒体内膜蛋白Higd1A在脂肪组织代谢稳态中的作用及其分子机制研究

脂肪组织代谢稳态的失衡，是导致肥胖及相关代谢病的重要因素。Higd1A是受缺氧诱导的定位于线粒体内膜的蛋白，参与呼吸链复合体组装，其在脂肪组织中的作用鲜有报道。我们前期研究发现：1） Higd1A 表达水平在脂肪细胞分化过程中、冷暴露刺激的小鼠脂肪组织中以及饮食诱导的肥胖小鼠脂肪组织中均上调；2）在脂肪细胞中敲低Higd1A，抑制棕色化基因表达、脂肪细胞氧耗及葡萄糖摄取，伴随线粒体结构异常。而在脂肪细胞中过表达Higd1A后作用相反；3）运用腺病毒载体在肥胖小鼠皮下脂肪组织中过表达Higd1A，可以提高小鼠胰岛素敏感性、促进皮下脂肪组织棕色化基因表达、抑制皮下脂肪组织炎症和纤维化基因表达。本项目将基于前期基础，结合细胞/分子生物学实验和动物模型，深入研究Higd1A在脂肪组织棕色化、糖脂稳态、纤维化、炎症等代谢稳态中的作用和分子机制，希望能为防治肥胖及相关代谢病提供新的理论依据和干预靶点。

The dysregulation of adipose tissue metabolic homeostasis is an important factor leading to obesity and its related metabolic disorders. Higd1A is a hypoxia-induced protein located on the mitochondrial inner membrane and is involved in the assembling of mitochondrial respiratory complex. But its role in adipose tissue is poorly understood. We found that 1) The expression level of Higd1A is elevated during adipocyte differentiation, after cold exposure in mice adipose tissue and the adipose tissue of high fat diet-fed mice; 2) Knockdown of Higd1A in adipocytes inhibited thermogenic gene expression, cellular oxygen consumption and glucose uptake, and caused abnormal morphology of the mitochondria, while overexpression of Higd1A in adipocytes resulted in opposite effects; 3) Adenovirus-mediated overexpression of Higd1A in the inguinal subcutaneous adipose tissue of high fat diet-fed mice improved the insulin sensitivity of the mice, enhanced the thermogenic genes expression and inhibited the inflammation and fibrosis genes expression in the inguinal subcutaneous adipose tissue. In this project, by performing cellular/molecular biology experiments and by using mice models, we will investigate the role and mechanism of Higd1A in regulating the metabolic homeostasis of adipose tissue. This study may provide new insights into the regulatory networks of adipose tissue metabolic homeostasis, including browning of adipocytes, carbohydrate and lipid metabolism, fibrosis and inflammation, and offer potential new targets for combating obesity and its related disorders.