Central Mechanisms Regulating Macronutrient Intake

调节大量营养素摄入的中心机制

• 批准号: 10266052
• 负责人: Matthew Joseph Potthoff
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266052
• 关键词: Address; Adult; Affect; Animal Model; Behavior; Body Weight; Body Weight decreased; Brain; Carbohydrates; Caring; Centers for Disease Control and Prevention (U.S.); Complex; Consumption; Data; Desire for food; Development; Diabetes Mellitus; Dopamine; Endocrine; Energy Intake; Epidemic; Fatty acid glycerol esters; Feedback; Feeding behaviors; Food; Food Energy; Genes; Glutamates; Goals; Grant; Health Care Costs; Healthcare; Hepatic; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; Intake; Lipids; Liver; Macronutrients Nutrition; Mediating; Medical; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Modeling; Motivation; Neuraxis; Neurons; Nucleus Accumbens; Nutrient; Obesity; Organism; Overweight; Oxytocin; Pathway interactions; Peripheral; Pharmacology; Physiological; Population; Production; Proteins; Public Health; Publishing; Quality of life; Regulation; Research; Rewards; Rodent; Role; Satiation; Signal Transduction; Single Nucleotide Polymorphism; Source; Synapses; Synaptic plasticity; Taste Perception; Taste preferences; Time; Ventral Tegmental Area; Veterans; Waist-Hip Ratio; Weight Gain; analog; blood glucose regulation; burden of illness; combat; compliance behavior; cost; economic cost; fibroblast growth factor 21; improved; in vivo; innovation; insight; liver function; mesolimbic system; metabolic profile; molecular targeted therapies; neural circuit; new therapeutic target; novel; novel therapeutics; obesity treatment; paraventricular nucleus; preference; receptor expression; social; sugar; sweet taste perception; tool

Obesity and diabetes are major public health issues that affect quality of life and also have high social and economic costs. According to the CDC, approximately 10% of U.S. adults have diabetes now and 33% are expected to have diabetes by 2050. At the same time, obesity has reached epidemic proportions, with over 60% of the U.S. population being overweight or obese. Therefore, there is a serious demand for the development of new therapeutics to combat obesity and diabetes. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that ameliorates metabolic dysfunction in a number of obese animal models and humans. Extended administration of FGF21 causes weight loss in rodents, and administration of FGF21 analogs to obese humans increases weight loss and improves metabolic profiles. Recently, we discovered that FGF21 functions physiologically and pharmacologically to suppress carbohydrate intake and sweet taste preference. Importantly, we and others have found that many of the beneficial effects of FGF21 are mediated through its actions on the central nervous system. However, the mechanism of FGF21 action in the brain and the neuronal target(s) for these effects has not been determined. The overall goal of this proposal is to identify the neural circuit(s) regulating FGF21-mediated suppression of carbohydrate intake. The aims of this grant are to 1) determine the direct neuronal target responsible for FGF21-mediated suppression of carbohydrate intake in vivo, 2) determine the role of oxytocin signaling in FGF21’s suppressive effect on simple sugar intake, and 3) determine the effect of FGF21 on the modulation of the mesolimbic dopamine system and feeding behavior. To accomplish these aims, we have generated novel animal models and tools to examine these experimental aims. These studies will provide new fundamental insights into the regulation of whole-body glucose homeostasis and food-related reward by peripheral endocrine signals acting on the central nervous system. In addition, these studies may identify novel therapeutic targets for the treatment of diabetes and obesity.

肥胖和糖尿病是影响生活质量的主要公共卫生问题，也具有很高的社会健康和 经济成本。根据疾病预防控制中心的数据，约有10％的美国成年人现在患有糖尿病，33％为 预计到2050年将患有糖尿病。与此同时，肥胖已经达到了流行比例 60％的美国人口超重或肥胖。因此，对 开发新的治疗剂来打击肥胖和糖尿病。成纤维细胞生长因子21（FGF21）是 在许多肥胖的动物模型和人类中改善代谢功能障碍的内分泌激素。 FGF21的扩展给药会导致啮齿动物的体重减轻，而施用FGF21类似物 肥胖人类增加体重减轻并改善代谢谱。最近，我们发现FGF21 物理和药物的功能可抑制碳水化合物的摄入量和甜味偏爱。 重要的是，我们和其他人发现，FGF21的许多有益作用都是通过其介导的 中枢神经系统的作用。但是，FGF21在大脑和神经元中作用的机制 这些影响的目标尚未确定。该提议的总体目标是确定中立 调节FGF21介导的碳水化合物摄入的电路。这笔赠款的目的是1） 确定负责FGF21介导的碳水化液摄入量的直接神经元靶标 体内，2）确定氧信号在FGF21对简单糖摄入的抑制作用中的作用，3） 确定FGF21对中唇多巴胺系统和喂养行为的调节的影响。到 完成这些目标，我们生成了新颖的动物模型和工具来检查这些实验 目标。这些研究将为整体葡萄糖调节提供新的基本见解 外周内分泌信号作用于中枢神经系统的稳态和食物有关的奖励。在 此外，这些研究可能确定用于治疗糖尿病和肥胖症的新型治疗靶标。