Regulation and Function of Adiponectin Oligomerization

摘要 受损的内质网（ER）和线粒体功能已被牵连在许多 肥胖引起的胰岛素抵抗和2型糖尿病的病因。然而， 机制仍有待充分阐明。我们已经鉴定出二硫键A氧化还原酶样蛋白或 DsbA-L作为脂肪细胞中脂联素组装和分泌的关键调节剂（Liu等人（2008）Proc. Nat. Acad. sci. USA，105，18302 - 07）。肥胖者脂肪组织中DsbA-L表达显著降低 受试者和肥胖动物模型。此外，脂肪特异性过表达DsbA-L促进脂联素 在体内多聚化，并减少高脂饮食诱导的胰岛素抵抗和脂肪肝， 脂联素依赖性机制（Liu等人（2012）Diabetes，61，2776 - 86）。然而，DsbA-L如何改善 胰岛素抵抗和能量稳态仍然是未知的。 在我们的初步研究中，一个新的观察结果是DsbA-L定位于ER和 线粒体此外，我们发现脂肪特异性敲除DsbA-L导致脂联素抑制， 多聚化和丰度，ER和线粒体功能受损，UCP1和其他棕色 脂肪组织中的基因表达，并减少能量消耗。综合来看，这些结果表明 DsbA-L可能通过促进脂联素的生物合成而发挥其抗肥胖和胰岛素增敏作用， 产热，这可能是通过改善ER和线粒体的完整性和功能来介导的。 我们将使用体外和离体方法以及脂肪特异性DsbA-L 过表达或敲除小鼠模型。这项研究将进一步加深我们对这些机制的理解。 潜在的肥胖诱导的胰岛素抵抗和能量稳态失调。本研究结果 还将导致确定新的药物靶点，用于创新的治疗策略， 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.