Regulation of Energy Homeostasis by FGF21

FGF21 对能量稳态的调节

基本信息

批准号：
10450711
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/10450711
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.

项目摘要 /摘要肥胖是包括血脂异常，心血管疾病在内的代谢疾病流行的主要因素疾病和II型糖尿病。大量研究表明，增加的能量消耗可以有效减轻体重。但是，没有当前的治疗化合物安全或有选择地激活能量支出。内分泌激素成纤维细胞生长因子21（FGF21）减少体重肥胖是通过增加能量消耗而不会影响体育锻炼的。此外，FGF21可能减少肥胖动物和人类患者的脂肪和体重。但是，机制 FGF21介导的能量消耗的增加尚未确定。来自我们实验室的工作，其他人有证明FGF21在中枢神经系统中起作用以促进体重减轻。另外，几行有证据表明，FGF21需要从脂肪衍生的马酮瘦素中完整的信号传导才能引起其对驾驶减肥的全部影响。最后，我们的初步数据表明，专有FGF21共同受体，β-klotho在弧形核us（ARC）和腹侧下丘脑（VMH）中表达瘦素在大脑中作用的位点，并且瘦素激活了VMH和弧。这就是我们假设FGF21信号至少部分地是在VMH和/或中对瘦素敏感的细胞弧调节能量消耗。该提案员工新型遗传小鼠模型，化学发生神经元的操纵和药物方法研究FGF21和能量稳态中心控制中的瘦素信号传导。通过这些研究，我们旨在识别新颖治疗肥胖和肥胖相关疾病的治疗靶标。