Regulation and Function of Adiponectin Oligomerization

脂联素寡聚化的调控和功能

• 批准号: 8827760
• 负责人: FENG LIU
• 金额: $ 33.46万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827760
• 关键词: Adipocytes; Adipose tissue; Affect; Anabolism; Animal Model; Biogenesis; Cell Survival; Complex; Development; Diabetes Mellitus; Diet; Drug Targeting; Electron Transport; Endoplasmic Reticulum; Energy Metabolism; Etiology; Fatty acid glycerol esters; Funding; Gene Expression; Genes; Glucose Intolerance; Grant; Health; Homeostasis; Human; In Vitro; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lead; Link; Maintenance; Mediating; Metabolic Diseases; Mitochondria; Molecular; Molecular Chaperones; Molecular Weight; Mus; NADH dehydrogenase (ubiquinone); Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Oxidoreductase; Oxygen Consumption; Play; Production; Protein Overexpression; Protein S; Proteins; Reactive Oxygen Species; Regulation; Research; Resveratrol; Role; Testing; Therapeutic; Thermogenesis; Thiazolidinediones; adiponectin; base; disulfide bond; endoplasmic reticulum stress; feeding; human subject; improved; in vivo; innovation; insulin sensitivity; mouse model; novel; novel therapeutics; obesity treatment; overexpression; oxidation; prevent; protein expression

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.

描述（由申请人提供）：内质网（ER）和线粒体功能受损与肥胖引起的胰岛素抵抗和2型糖尿病的许多病因有关。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. 阿卡德。科学。美国，105, 18302-07)。在肥胖人类受试者和肥胖动物模型中，脂肪组织中的 DsbA-L 表达显着降低。此外，DsbA-L 的脂肪特异性过度表达促进体内脂联素多聚化，并通过脂联素依赖性机制减少高脂饮食诱导的胰岛素抵抗和肝脂肪变性（Liu et al. (2012) Diabetes, 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。我们初步研究中的一个新观察结果是，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 会导致脂联素多聚化和丰度受到抑制，内质网和线粒体功能受损，脂肪组织中 UCP1 和其他棕色基因表达减少，并减少能量消耗。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生热作用发挥其抗肥胖和胰岛素增敏作用，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检验这一假设。这项研究将进一步了解肥胖引起的胰岛素抵抗和能量稳态失调的潜在机制。这项研究的结果还将有助于确定新的药物靶点，用于预防肥胖引起的代谢紊乱的创新治疗策略。