Regulation of Energy Homeostasis by FGF21

项目概要/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、心血管疾病和糖尿病。 疾病和II型糖尿病。许多研究表明，增加能量消耗可以有效地 减轻体重。然而，目前没有治疗化合物安全地或选择性地激活能量 支出内分泌激素成纤维细胞生长因子21（FGF 21）在哺乳期间降低体重。 肥胖通过增加能量消耗而不影响身体活动。此外，FGF 21有效地 减少肥胖动物和人类患者的脂肪和体重。然而， FGF 21介导的能量消耗增加尚未确定。我们实验室的工作和其他人的工作 研究表明，FGF 21在中枢神经系统中起作用，以促进体重减轻。此外，几条线路 有证据表明，FGF 21需要来自脂肪源性激素瘦素的完整信号传导， 对驾驶减肥的全面影响。最后，我们的初步数据表明，专性FGF 21共- 受体β-klotho在弓状核（ARC）和下丘脑腹内侧（VMH）中表达， 瘦素在大脑中的作用位点，瘦素激活VMH中β-klotho表达细胞的信号传导， 弧因此，我们假设FGF 21至少部分地向VMH和/或VMH中的瘦素敏感细胞发出信号。 ARC调节能量消耗。该建议采用了新的遗传小鼠模型，化学遗传学 神经元的操作，以及研究FGF 21和TGF-β 1之间串扰的药理学方法。 瘦素信号在能量稳态的中枢控制中的作用。通过这些研究，我们的目标是确定新的 用于治疗肥胖症和肥胖症相关疾病的治疗靶点。

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.