Regulation of Energy Homeostasis by FGF21

FGF21 对能量稳态的调节

基本信息

批准号：
10118923
负责人：
Matthew Joseph Potthoff
金额：
$ 52.41万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10118923
关键词：
Acute Adipocytes Adipose tissue Adult Affect Animal Model Animals Automobile Driving Back Body Temperature Body Weight Body Weight decreased Brain Brain region Brown Fat Calcium Cardiovascular Diseases Cells Data Disease Dyslipidemias Electrophysiology (science)Endocrine Energy Intake Energy Metabolism Enterobacteria phage P1 Cre recombinase Epidemic Fat Body Genetic Goals Homeostasis Hormonal Hormones Human Hydrogen Hypertension Hypothalamic structure Image Inner mitochondrial membrane Insulin Knock-out Leptin Mediating Metabolic Metabolic Diseases Mus Nerve Neuraxis Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Pathway interactions Patients Peripheral Pharmacogenetics Pharmacology Physical activity Population Process Publishing Regulation Research Signal Transduction Site Slice Structure of nucleus infundibularis hypothalami Therapeutic Thermogenesis Tissues Work analog blood glucose regulation cellular targeting chemical release fasting glucose fibroblast growth factor 21 flexibility glutamatergic signaling improved in vivo innovation insulin sensitivity leptin receptor metabolic rate mitochondrial uncoupling protein mouse model neural circuit neural network new therapeutic target novel novel therapeutic intervention obesity treatment promoter receptor receptor expression response uncoupling protein 1

项目摘要

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.

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、心血管疾病大量研究表明，增加能量消耗可以有效地预防疾病和 II 型糖尿病。然而，目前没有安全或选择性激活能量的治疗化合物。内分泌激素成纤维细胞生长因子 21 (FGF21) 会降低体重。通过增加能量消耗而不影响体力活动，FGF21 可以有效抑制肥胖。减少肥胖动物和人类患者的脂肪和体重然而，其机制。我们实验室和其他实验室的工作尚未确定 FGF21 介导的能量消耗增加。 FGF21 作用于中枢神经系统，促进减肥。大量证据表明，FGF21 需要来自脂肪源性激素瘦素的完整信号传导，才能激发其作用。最后，我们的初步数据表明，专性 FGF21 协同作用。 β-klotho 受体在弓状核 (ARC) 和下丘脑腹内侧 (VMH) 中表达，初级瘦素在大脑中的作用位点，并且瘦素激活 VMH 和 β-klotho 表达细胞中的信号传导因此，我们至少部分地向 VMH 和/或中的瘦素敏感细胞发出 FGF21 信号。 ARC 调节能量消耗该提案采用新型遗传小鼠模型，即化学遗传学。神经元的操作以及研究 FGF21 和 FGF21 之间串扰的药理学方法通过这些研究，我们旨在识别新的瘦素信号在能量稳态的中央控制中的作用。治疗肥胖和肥胖相关疾病的治疗靶点。