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诱导的胰岛素抵抗和2型糖尿病病因有关。然而，潜在的分子机制仍有待充分阐明。我们已经鉴定了二硫键A氧化还原酶样蛋白或DsbA-L作为脂肪细胞中脂连蛋白组装和分泌的关键调节剂（Liu等人（2008）Proc. Nat. Acad. Sci. USA，105，18302-07）。脂肪组织中的DsbA-L表达在肥胖的人类受试者和肥胖的动物模型中显著降低。此外，DsbA-L的脂肪特异性过表达促进体内脂联素多聚化，并通过脂联素依赖性机制降低高脂肪饮食诱导的胰岛素抵抗和肝脂肪变性（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未知。在我们的初步研究中，一个新的观察是，DsbA-L是本地化的ER和线粒体。此外，我们发现脂肪特异性敲除DsbA-L导致脂联素多聚化和丰度抑制，ER和线粒体功能受损，脂肪组织中UCP 1和其他棕色基因表达减少，能量消耗减少。总之，这些结果表明，DsbA-L可能发挥其抗肥胖和胰岛素增敏作用，通过促进脂联素的生物合成和产热，这可能是通过改善ER和线粒体的完整性和功能介导的。我们将通过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来测试这一假设。本研究将进一步加深我们对肥胖引起的胰岛素抵抗和能量稳态失调的机制的理解。这项研究的结果也将导致识别新的药物靶点，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.