Regulation and Function of Adiponectin Oligomerization

摘要 内质网(ER)和线粒体功能受损与许多 肥胖导致的胰岛素抵抗和2型糖尿病的病因学。然而，潜在的分子 其作用机制尚待充分阐明。我们已经鉴定出二硫键A氧化还原酶样蛋白或 DsbA-L作为脂肪细胞脂联素组装和分泌的关键调节因子(Liu等人，2008年)。纳特。 阿卡德。SCI。美国，第105,18302-07)。肥胖人群脂肪组织中DsbA-L的表达显著降低 肥胖的受试者和动物模型。此外，脂肪特异性过表达DsbA-L促进了脂联素 体内多聚体和减少高脂饮食诱导的胰岛素抵抗和肝骨病 脂联素依赖机制(Liu et al.(2012)糖尿病，61,2776-86)。然而，DsbA-L如何提高 胰岛素抵抗和能量平衡仍不清楚。 在我们的初步研究中，一个新的观察结果是DsbA-L在内质网和内质网都有定位 线粒体。此外，我们还发现脂肪特异的DsbA-L基因敲除导致脂联素被抑制 多聚体和丰度，内质网和线粒体功能受损，UCP1和其他棕色 脂肪组织中的基因表达，并降低能量消耗。综上所述，这些结果表明 DsbA-L可能通过促进脂联素生物合成和胰岛素增敏作用发挥其抗肥胖和胰岛素增敏作用。 产热，这可能是通过改善内质网和线粒体的完整性和功能来调节的。 我们将通过使用体外和体外方法以及脂肪特异性DsbA-L来验证这一假说 过度表达或敲除小鼠模型。这项研究将进一步加深我们对这一机制的理解 肥胖导致的胰岛素抵抗和能量平衡失调。这项研究的结果 还将导致新药靶点的确定(S)进行创新治疗策略，以预防 肥胖引起的代谢紊乱。

Abstract Impaired endoplasmic reticulum (ER) and mitochondrial function has been implicated in many of the obesity-induced etiology of insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms remain to be fully elucidated. We have identified Disulfide bond A oxidoreductase-like protein or DsbA-L as a critical regulator of adiponectin assembly and secretion in adipocytes (Liu et al (2008) Proc. Nat. Acad. Sci. USA, 105, 18302-07). DsbA-L expression in adipose tissues is significantly reduced in obese human subjects and animal models of obesity. In addition, fat-specific overexpression of DsbA-L promoted adiponectin multimerization in vivo and reduced high fat diet-induced insulin resistance and hepatosteatosis via an adiponectin-dependent mechanism (Liu et al. (2012) Diabetes, 61, 2776-86). However, how DsbA-L improves insulin resistance and energy homeostasis remains unknown. A novel observation made in our preliminary study is that DsbA-L is localized in both the ER and mitochondria. In addition, we have found that fat-specific knockout of DsbA-L led to suppressed adiponectin multimerization and abundance, impaired ER and mitochondrial function, decreased UCP1 and other brown gene expression in adipose tissues, and reduced energy expenditure. Taken together, these results suggest that DsbA-L may exert its anti-obesity and insulin sensitizing roles by promoting adiponectin biosynthesis and thermogenesis, which may be mediated by improving the integrity and function of both the ER and mitochondria. We will test this hypothesis by using in vitro and ex vivo approaches as well as fat-specific DsbA-L overexpression or knockout mouse models. This research will further our understanding of the mechanisms underlying obesity-induced insulin resistance and dysregulation of energy homeostasis. Results from this study will also lead to the identification of new drug target(s) for innovative therapeutic strategies to prevent obesity-induced metabolic disorders.