Role of Adipokine FABP4 in Glucoregulation and Counter Regulatory Responses

项目总结 尽管反调节机制对于对抗饥饿和低血糖很重要，但一个重要的 这种适应性网络的组成部分--脂肪组织--仍未得到充分研究。它在功能上和进化上 可以想象，在禁食期间必须存在信号来将这一主要能量来源整合到计数器的其余部分- 监管网络。主要脂肪细胞脂肪酸结合蛋白(FABP)成员FABP4由 在禁食和肥胖的情况下，脂肪细胞的循环水平会上升，荷尔蒙作用于肝脏，促进 肝脏葡萄糖的产生。通过这种方式，肥胖动物体内循环中的高水平FABP4似乎 有一种让人想起高血糖素血症的效果，这是糖尿病状态的特征。这样做的目的是 建议了解循环中FABP4在介导异常肝糖异生中的作用。 糖尿病的情况。我们的主要假设是，FABP4增强了胰高血糖素信号的作用，是一种 是反调节机制的关键组成部分，也是肥胖相关糖尿病发展的中介者。这个 目前提案中描述的研究将通过确定FABP4是否需要 通过鉴定潜在的FABP4-胰高血糖素-胰高血糖素受体介导高血糖素血症对糖尿病的影响 (GCGR)物理相互作用，并通过定义FABP4信号在肝细胞中传播的机制。 这些实验将利用遗传小鼠模型以及生化和基于细胞的分析来剖析 循环FABP4的功能及其与胰高血糖素信号通路的相互作用这一贡献是巨大的 因为它将阐明分子信号通路，这些信号通路构成了 肥胖和糖尿病，并可能导致新的治疗策略的发展。这项工作的创新之处 在于确定了一种新的内分泌调节机制--脂肪因子与细胞因子的相互作用 一种将脂肪组织与反调节机制联系在一起的糖调节荷尔蒙--并携带着重要的 对代谢性疾病发病机制的影响。

PROJECT SUMMARY Despite importance of counter-regulatory mechanisms to combat starvation and hypoglycemia, a significant component of this adaptive network, adipose tissue, remains understudied. It is functionally and evolutionarily conceivable that signals must exist to integrate this major source of energy during fasting to rest of the counter- regulatory network. The major adipocyte fatty acid binding protein (FABP) member FABP4, is secreted from adipocytes circulating levels rise in fasting and in the context of obesity, and the hormone acts on the liver to promote hepatic glucose production. In this way, the high levels of circulating FABP4 that occur in obese animals appear to have an effect reminiscent of the hyperglucagonemia that characterizes the diabetic state. The objective of this proposal is to understand the contribution of circulating FABP4 in mediating aberrant hepatic gluconeogenesis in the diabetic condition. Our overarching hypothesis is that FABP4 potentiates the action of glucagon signaling and is a critical component of counter-regulatory machinery and mediator of the development of obesity-related diabetes. The studies described in the current proposal will test this hypothesis by determining whether FABP4 is required to mediate the effect of hyperglucagonemia in diabetes, by characterizing a potential FABP4-glucagon-glucagon receptor (GCGR) physical interaction, and by defining the mechanism by which the FABP4 signal is propagated in hepatocytes. These experiments will make use of genetic mouse models and biochemical and cell-based assays to dissect the function of circulating FABP4 and its interaction with the glucagon signaling pathway. This contribution is significant because it will illuminate the molecular signaling pathways that underlie the well-established connection between obesity and diabetes, and may lead to the development of novel therapeutic strategies. The innovation of this work lies in pinpointing a novel mechanism of endocrine regulation - the interaction between an adipokine and a glucoregulatory hormone that links the adipose tissue to counter-regulatory mechanisms- and carries important implications for metabolic disease pathogenesis.