RBP4-Transthyretin Interactions in Insulin Resistant States

描述(由申请人提供)： 胰岛素抵抗(即胰岛素抵抗)是2型糖尿病的一个重要致病特征。即使没有糖尿病，胰岛素抵抗也是心血管疾病和过早死亡的主要风险因素。导致胰岛素抵抗的两个主要原因是肥胖和遗传易感性。我们最近发现，在胰岛素抵抗的小鼠和人类，血清视黄醇结合蛋白(RBP4)浓度升高。在一系列动物模型中，我们证明了增加血清RBP4会导致胰岛素抵抗和葡萄糖耐量异常，而降低血清RBP4则可以改善胰岛素敏感性和糖耐量。因此，RBP4可能在胰岛素抵抗中起因果作用。脂肪组织中RBP4的表达增加可能是胰岛素抵抗状态下血清RBP4升高的部分原因。然而，其他因素可能会调节RBP4的血清浓度。血清蛋白转甲状腺素与RBP4结合，在稳定血清中RBP4方面起着关键作用。用一种药物(芬维甲素)阻断RBP4与转甲状腺素的结合可以降低循环中的RBP4水平，改善胰岛素敏感性，并降低血糖。因此，决定RBP4与转甲状腺素结合程度的因素可能在胰岛素抵抗的发生发展中起重要作用。初步研究表明，在胰岛素抵抗的小鼠和人类中，转甲状腺激素水平都会升高。已知转甲状腺素经历了几种不同的翻译后修饰，这些修饰可能会潜在地影响其与RBP4的结合亲和力。初步发现，在肥胖和胰岛素抵抗方面，这些修饰的模式发生了变化。有待检验的假设是，转甲肾上腺素浓度或翻译后修饰是否调节血清RBP4浓度和/或RBP4在胰岛素抵抗状态下的作用。在体外和在小鼠体内的研究都被提议用来评估转甲状腺蛋白在调节RBP4中的作用。 胰岛素抵抗是2型糖尿病和心血管疾病的主要原因。我们实验室最近的工作已经确定血清视黄醇结合蛋白(RBP4)是人类和小鼠胰岛素抵抗的潜在原因。胰岛素抵抗与循环中RBP4水平升高有关。脂肪中RBP4产量的增加似乎是人类和小鼠循环中RBP4增加的一个重要来源。然而，血清蛋白转甲状腺素也在稳定循环中的RBP4方面发挥作用。这项拟议的工作将从生物化学相互作用、培养细胞的代谢效应和小鼠的代谢效应等方面研究转甲肾上腺素和RBP4之间的相互作用。

DESCRIPTION (provided by applicant): Resistance to the action of insulin (i.e., insulin resistance) is a key pathogenic feature of type 2 diabetes. Even without diabetes, insulin resistance is a major risk factor for cardiovascular disease and early death. The two major causes of insulin resistance are obesity and genetic predisposition. We recently discovered that serum retinol binding protein (RBP4) concentrations are elevated in insulin resistant mice and humans. In a series of animal models we demonstrated that increasing serum RBP4 causes insulin resistance and glucose intolerance, whereas lowering serum RBP4 improves insulin sensitivity and glucose tolerance. Therefore, RBP4 may play a causal role in insulin resistance. Increased expression of RBP4 in adipose tissue may be partly responsible for elevated serum RBP4 in insulin resistant states. However, other factors may regulate serum concentrations of RBP4. The serum protein, transthyretin, binds RBP4 and plays a critical role in stabilizing RBP4 in serum. Treating mice with a drug (fenretinide) that blocks binding of RBP4 to transthyretin lowers circulating RBP4 levels, improves insulin sensitivity, and lowers blood glucose. Therefore, factors that determine how strongly RBP4 binds transthyretin may be important in the development of insulin resistance. Preliminary studies indicate that transthyretin levels are elevated in insulin resistant mice and in humans. Transthyretin is known to undergo several different post-translational modifications that could potentially influence its binding affinity with RBP4. Preliminary findings indicate that the pattern of these modifications is altered in obesity and insulin resistance. The hypothesis to be tested is whether transthyretin concentrations or post- translational modifications regulate serum RBP4 concentrations and/or RBP4 action in insulin resistant states. Both in vitro and in vivo studies in mice are proposed to evaluate the role of transthyretin in regulating RBP4. Insulin resistance is a major cause of type 2 diabetes and cardiovascular disease. Recent work in our laboratory has identified serum retinol binding protein (RBP4) as a potential cause of insulin resistance in humans and in mice. Insulin resistance is associated with increased levels of RBP4 in the circulation. Increased production of RBP4 in fat appears to be an important source of increased circulating RBP4 in humans and in mice. However, the serum protein, transthyretin, also plays a role in stabilizing RBP4 in circulation. The proposed work will study the interaction between transthyretin and RBP4 in terms of their biochemical interactions, metabolic effects in cultured cells, and metabolic effects in mice.