Regulation of Carbohydrate Metabolism by FGF21 Action on Brown Adipose Tissue

 描述(申请人提供)：胰岛素抵抗是代谢疾病流行的主要因素，包括血脂异常、高血压和2型糖尿病。根据美国疾病控制与预防中心的数据，目前约有10%的美国成年人患有糖尿病，预计到2050年将有33%的人患有糖尿病。因此，迫切需要开发新的治疗方法来增加胰岛素敏感性。成纤维细胞生长因子21(FGF21)是一种内分泌激素，是一种有效的胰岛素增敏剂。与其他通过减少异位脂质堆积间接提高胰岛素敏感性的胰岛素增敏剂不同，FGF21具有直接增强胰岛素敏感性的独特能力。我们最近证明，循环中的FGF21水平是在过度喂养期间从肝脏产生的，其功能是促进棕色脂肪组织(BAT)中胰岛素刺激的葡萄糖处置。这项资助的目的是1)确定FGF21对BAT的作用对FGF21的胰岛素增敏作用的贡献，以及2)确定FGF21增强棕色脂肪细胞胰岛素敏感性的机制。为了实现这些目标，我们提出了几种实验方法。在具体目标1中，我们将利用新的动物模型来灭活、重新激活或结构性激活体内特定脂肪储存库的FGF21信号，以获得组织特异性的胰岛素敏感性效应。在特定的目标2中，我们将研究FGF21增强棕色脂肪细胞胰岛素刺激的葡萄糖摄取的机制。此外，我们还将评估BAT中胰岛素刺激的葡萄糖摄取在FGF21体内降糖作用中的作用。这些研究具有重要意义，因为它们将为FGF21的作用机制提供新的信息，也为调节全身葡萄糖稳态的机制提供了基本的见解。

 DESCRIPTION (provided by applicant): Insulin resistance is a major contributor to the epidemic of metabolic diseases including dyslipidemia, hypertension and type 2 diabetes. According to the CDC, approximately 10% of U.S. adults have diabetes now and 33% are expected to have diabetes by 2050. Therefore, there is a serious demand for the development of new therapeutics to increase insulin sensitivity. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is a potent insulin sensitizer. Unlike other insulin sensitizers that indirectly improve insulin sensitivity by reducing ectopic lipid accumulation, FGF21 has the unique ability to directly enhance insulin sensitivity. We recently demonstrated that circulating FGF21 levels are produced from the liver during overfeeding and function to enhance insulin-stimulated glucose disposal in brown adipose tissue (BAT). The aims of this grant are to 1) determine the contribution of FGF21 action on BAT to the insulin-sensitizing effects of FGF21, and 2) determine the mechanism by which FGF21 enhances insulin sensitivity in brown adipocytes. To accomplish these aims, we propose several experimental approaches. In specific aim 1, we will utilize novel animal models to inactivate, reactivate or constitutively activate FGF21 signaling to specific adipose depots in vivo to access tissue-specific effects on insulin sensitivity. In specific aim 2, we will examine the mechanism whereby FGF21 enhances insulin-stimulated glucose uptake in brown adipocytes. In addition, we will evaluate the contribution of insulin-stimulated glucose uptake in BAT to the glucose lowering effects of FGF21 in vivo. These studies are significant because they will provide new information on the mechanism of FGF21 action, and also provide fundamental insight into the mechanisms regulating whole-body glucose homeostasis.