Regulation and Function of Adiponectin Oligomerization

描述(由申请人提供)：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型糖尿病的病因有关。然而，其潜在的分子机制仍未完全阐明。我们已经确定二硫键A氧化还原酶样蛋白或DsbA-L是脂肪细胞中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)。在肥胖受试者和肥胖动物模型中，DsbA-L在脂肪组织中的表达显著降低。此外，脂肪特异性过表达DsbA-L促进了体内脂联素的多聚化，并通过脂联素依赖的机制减少了高脂饮食诱导的胰岛素抵抗和肝骨病(Liu等人。(2012)糖尿病，61,2776-86)。然而，DsbA-L如何改善胰岛素抵抗和能量稳态仍不清楚。在我们的初步研究中发现，DsbA-L定位于内质网和线粒体中。此外，我们还发现，脂肪特异的DsbA-L基因敲除导致脂联素的多聚化和丰度受到抑制，内质网和线粒体功能受损，UCP1等棕色基因在脂肪组织中的表达减少，能量消耗减少。综上所述，DsbA-L可能通过促进脂联素的生物合成和产热而发挥其抗肥胖和胰岛素增敏作用，其机制可能与改善内质网和线粒体的完整性和功能有关。我们将使用体外和体外方法以及脂肪特异性的DsbA-L过表达或基因敲除小鼠模型来验证这一假说。这项研究将进一步加深我们对肥胖导致的胰岛素抵抗和能量平衡失调的机制的理解。这项研究的结果还将导致确定新的药物靶点(S)，用于预防肥胖引起的代谢紊乱的创新治疗策略。

DESCRIPTION (provided by applicant): 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.