Regulation of Energy Homeostasis by FGF21

项目摘要/摘要 肥胖是代谢性疾病流行的主要原因，包括血脂异常、心血管疾病 疾病和II型糖尿病。大量研究表明，增加能量消耗可以有效地 减轻体重。然而，目前还没有安全或选择性地激活能量的治疗化合物。 支出。内分泌激素成纤维细胞生长因子21(FGF21)在 在不影响体力活动的情况下，通过增加能量消耗来肥胖。此外，FGF21还能有效地 减少肥胖动物和人类患者的脂肪和体重。然而，用于 FGF21介导的能源支出增加尚未确定。我们实验室和其他实验室的研究成果 研究表明，FGF21在中枢神经系统起作用，促进减肥。此外，还有几行 大量证据表明，FGF21需要来自脂肪衍生激素瘦素的完整信号，才能引发其 对推动减肥的全面效果。最后，我们的初步数据表明，专有的FGF21协同- β-klotho受体主要表达于弓状核和下丘脑腹内侧核。 瘦素在脑中的作用部位，以及瘦素激活VMH和β-klotho表达细胞的信号转导 弧形。因此，我们假设FGF21至少部分地向VMH和/或Leptin敏感细胞发出信号 弧光来调节能量消耗。这项建议采用了新的遗传小鼠模型，化学遗传学 神经元的操纵，以及研究FGF21和FGF21之间的串扰的药理学方法 瘦素信号在能量稳态的中枢控制中的作用。通过这些研究，我们的目标是确定小说 治疗肥胖和肥胖相关疾病的治疗目标。

Project Summary / Abstract Obesity is a major contributor to the epidemic of metabolic diseases including dyslipidemia, cardiovascular disease, and type II diabetes. Numerous studies suggest that increasing energy expenditure can effectively decrease body weight. However, no current therapeutic compounds safely or selectively activate energy expenditure. The endocrine hormone fibroblast growth factor 21 (FGF21) decreases body weight during obesity by increasing energy expenditure without affecting physical activity. Moreover, FGF21 potently decreases both fat and body mass in obese animals and human patients. However, the mechanism for FGF21-mediated increases in energy expenditure has not been identified. Work from our lab and others have demonstrated that FGF21 acts in the central nervous system to promote weight loss. In addition, several lines of evidence suggest that FGF21 requires intact signaling from the adipose-derived hormone, leptin, to elicit its full effects on driving weight loss. Finally, our preliminary data demonstrates that the obligate FGF21 co- receptor, β-klotho, is expressed in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH), primary sites of leptin action in the brain, and that leptin activates signaling in β-klotho-expressing cells in the VMH and ARC. Thus, we hypothesize that FGF21 signals, at least in part, to leptin-sensitive cells in the VMH and/or ARC to modulate energy expenditure. This proposal employs novel genetic mouse models, chemogenetic manipulation of neurons, and pharmacological approaches to investigate the crosstalk between FGF21 and leptin signaling in the central control of energy homeostasis. Through these studies we aim to identify novel therapeutic targets for the treatment of obesity and obesity-associated disorders.