The role of adipocyte apoptosis in development of insulin resistance and non-alcoholic fatty liver disease (NAFLD)

肥胖、2型糖尿病和非酒精性脂肪性肝病（NAFLD）密切相关，并已在世界范围内达到流行病的程度。有人提出，脂肪组织中的低度炎症可能有助于胰岛素抵抗的发展。然而，脂肪组织炎症、胰岛素抵抗和NAFLD之间的联系机制仍然知之甚少。在我们自己的研究中，白色和棕色脂肪细胞在缺氧处理下表现出不同的代谢活性。客座实验室主要研究肥胖、脂肪炎症、NAFLD和胰岛素抵抗之间的联系机制。他们在肥胖小鼠和人类的脂肪组织中发现了促凋亡表型。脂肪细胞中的脂肪积累和氧化应激（活性氧的过量产生），特别是线粒体，都导致脂肪细胞凋亡。脂肪细胞中促凋亡分子Bid的失活与脂肪组织炎症的减少以及胰岛素抵抗有关。因此，本研究将探讨脂肪细胞凋亡在脂肪肝发生发展中的影响及机制。除了获得技术技能的体外研究外，还计划在小鼠体内进行全身和组织特异性敲除Bid的研究。这一建议的结果不仅可能为肥胖、2型糖尿病、NAFLD和其他人类疾病的联系机制提供新的见解，而且可能转化为治疗这些疾病的新治疗策略。

Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are closely associated and have reached epidemic proportions worldwide. It has been proposed that low grade inflammation in fat (adipose) tissue may contribute to the development of insulin resistance. However, mechanisms linking adipose tissue inflammation, insulin resistance, and NAFLD remain poorly understood. White and brown adipocytes exhibited different metabolic activity upon hypoxic treatment in our own studies. The guest laboratory is focusing on the mechanisms linking obesity, adipose inflammation, NAFLD, and insulin resistance. They found a pro-apoptotic phenotype in adipose tissue of obese mice and humans. Both accumulation of fat in fat cells and oxidative stress (excessive production of reactive oxygen species) specifically from mitochondria led to apoptosis in adipocytes. Inactivation of the proapoptotic molecule Bid in adipocytes is associated with decreased inflammation in adipose tissue as well as insulin resistance. Therefore the presented proposal will address the influence and mechanisms of adipocyte apoptosis in the development and progression of fatty liver disease. Beside in vitro studies to achieve technical skills mainly in vivo studies in mice with whole-body and tissue-specific knockout of Bid are planned.The results of this proposal may not only shed new insights into the mechanisms linking obesity, type 2 diabetes, NAFLD, and other human diseases but also could translate into new therapeutic strategies to treat these conditions.