The novel role of FGF21 in mediating sex-dependent responses to dietary macronutrients

FGF21 在介导对膳食常量营养素的性别依赖性反应中的新作用

基本信息

批准号：
10215500
负责人：
Karen Ryan
金额：
$ 38.27万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215500
关键词：
Address Adipocytes Adipose tissue Adrenergic Agents Adverse effects Aging Agreement Biochemical Biomedical Research Body Composition Body Weight Body Weight decreased Body fat Brain Clinical Complex Data Diabetes Mellitus Diet Dietary Intervention Dietary Proteins Dose Eating Energy Metabolism Environment Enzymes Equilibrium Estrogen Receptor beta Estrogens Fatty acid glycerol esters Female Genetic Goals Human Hypothalamic structure Indirect Calorimetry Intervention Isotopes Knowledge Light Link Lipids Lipolysis Liver Macronutrients Nutrition Measurement Mediating Metabolic Metabolic Diseases Metabolic syndrome Mission Molecular Mus Neuroendocrine Cell Neurons Neurosecretory Systems Norepinephrine Nutritional Obesity Outcome Ovariectomy Patients Pharmaceutical Preparations Pharmacology Physiological Plasma Play Polypeptide Hormones Proteins Public Health Publishing Rattus Regulation Research Risk Role Sex Differences Signal Transduction Stress Testing Therapeutic Thermogenesis Time Tissues Tracer Triglycerides Tweens United States National Institutes of Health Woman Work base clinical application comorbidity diabetes control dietary experimental study fibroblast growth factor 21 genetic manipulation glucose metabolism glucose tolerance improved insight interest lipid metabolism male men novel nutrition pre-clinical preclinical study preservation programs receptor response sex sexual dimorphism suprachiasmatic nucleus targeted delivery therapeutic target therapy development

项目摘要

Because sex differences exist in almost all aspects of the metabolic syndrome, treatments developed using only male subjects elicit a disproportionate risk for adverse, off-target, or simply ineffective outcomes among female patients. Yet the vast majority of pre-clinical biomedical research focuses only on males. Fibro- blast growth factor 21 (FGF21), a polypeptide hormone produced by the liver in response to nutritional stress, is a promising target for treatment of metabolic disease. In males, administration at pharmacologic doses im- proves glucose tolerance, and reduces body weight and body fat by increasing sympathetic outflow to adipose tissue, increasing thermogenesis. Consequently, several major companies are developing FGF21-based com- pounds for clinical use. Yet surprisingly little is known about the metabolic actions of FGF21 in females. Our recently published and preliminary data strongly support that FGF21 functions as a key mechanism facilitating the sexually dimorphic metabolic response to dietary protein ‘dilution’—a novel nutritional intervention eliciting weight loss and improved glucose and lipid metabolism in male mice, rats and humans. In this project, we plan to address the next critical step, by identifying specific neuroendocrine and cell-autonomous mechanisms by which FGF21 elicits divergent metabolic responses in males and females. The overarching hypothesis in this proposal is that, in the presence of estrogen receptor-beta, FGF21 signaling in the hypothalamus increases the sympathetic drive to adipose tissue in males but not females, and FGF21 signaling in the adipocyte inhibits the catabolic response to adrenergic stimulation in females but not males. We will test hypothesis using pharmaco- logic, genetic and nutritional manipulations of FGF21 signaling in the brain (Aim 1) and adipose tissue (Aim 2) of male and female mice, together with indirect calorimetry, and isotopic tracer-assisted measurements of lipid turnover. These experiments are expected to delineate neuroendocrine and molecular mechanisms contrib- uting to the sexually dimorphic regulation of fat mass, thereby facilitating the appropriate and targeted delivery of nutritional and pharmacological interventions in obesity and metabolic disease. In light of the considerable interest in FGF21 itself as a therapeutic target, we are surprised to note that almost nothing is known about its metabolic effects in female subjects. Therefore, this work is not only physiologically important, but it will also provide new insights in the clinical application of FGF21-based therapeutics in both men and women.

由于代谢综合征的几乎所有方面都存在性别差异，因此开发了治疗方法仅使用男性受试者会导致不良、脱靶或根本无效结果的不成比例的风险然而，绝大多数临床前生物医学研究仅关注男性患者。胚细胞生长因子 21 (FGF21)，一种由肝脏响应营养应激而产生的多肽激素，是治疗男性代谢疾病的一个有前途的目标，以药理学剂量给药是重要的。证明葡萄糖耐量，通过增加交感神经向脂肪的流出来减少体重和体脂经过测试，几家大公司正在开发基于 FGF21 的化合物。然而，令人惊讶的是，我们对 FGF21 在女性体内的代谢作用知之甚少。最近发布的初步数据强烈支持 FGF21 作为促进对饮食蛋白质“稀释”的两性代谢反应——一种新颖的营养干预措施在这个项目中，我们计划减轻雄性小鼠、大鼠和人类的体重并改善葡萄糖和脂质代谢。通过识别特定的神经内分泌和细胞自主机制来解决下一个关键步骤 FGF21 在男性和女性中引起不同的代谢反应。提议认为，在存在雌激素受体 β 的情况下，下丘脑中的 FGF21 信号传导会增加男性而非女性的交感神经对脂肪组织产生驱动力，并且脂肪细胞中的 FGF21 信号传导抑制女性而非男性对肾上腺素刺激的分解代谢反应我们将使用药物来检验假设。大脑（目标 1）和脂肪组织（目标 2）中 FGF21 信号传导的逻辑、遗传和营养操作雄性和雌性小鼠的实验，以及间接量热法和同位素示踪剂辅助的脂质测量这些实验预计将描述神经内分泌和分子机制。利用脂肪量的性别二态性调节，从而促进适当和有针对性的输送肥胖和代谢疾病的营养和药物干预。尽管人们对 FGF21 本身作为治疗靶点感兴趣，但我们惊讶地发现，人们对其几乎一无所知因此，这项工作不仅具有生理意义，而且也具有重要意义。为基于 FGF21 的疗法在男性和女性的临床应用提供了新的见解。