Central Mechanisms Regulating Macronutrient Intake

调节大量营养素摄入的中心机制

• 批准号: 9974289
• 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/9974289
• 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重大公共卫生问题，也具有很高的社会影响和影响。 据 CDC 称，目前大约 10% 的美国成年人患有糖尿病，其中 33% 患有糖尿病。 预计到 2050 年，人们将患上糖尿病。与此同时，肥胖症已达到流行病的程度，超过 60%的美国人口超重或肥胖，因此对产品的需求很大。 开发对抗肥胖和糖尿病的新疗法是一种新疗法。 内分泌激素，可改善许多肥胖动物模型和人类的代谢功能障碍。 延长给予 FGF21 会导致啮齿类动物体重减轻，给予 FGF21 类似物会导致啮齿类动物体重减轻 最近，我们发现 FGF21 可以促进肥胖人群的减肥并改善代谢状况。 具有生理和药理作用，可抑制碳水化合物的摄入和甜味偏好。 重要的是，我们和其他人发现 FGF21 的许多有益作用是通过其介导的 然而，FGF21 在大脑和神经元中的作用机制。 这些影响的目标尚未确定。该提案的总体目标是确定神经网络。 调节 FGF21 介导的碳水化合物摄入抑制的电路 此项资助的目的是 1) 确定负责 FGF21 介导的碳水化合物摄入抑制的直接神经靶标 体内，2) 确定催产素信号传导在 FGF21 对单糖摄入的抑制作用中的作用，以及 3) 确定 FGF21 对中脑边缘多巴胺系统和进食行为调节的影响。 为了实现这些目标，我们已经生成了新颖的动物模型和工具来检查这些实验 这些研究将为全身葡萄糖的调节提供新的基本见解。 通过作用于中枢神经系统的外周内分泌信号实现体内平衡和与食物相关的奖励。 此外，这些研究可能会确定治疗糖尿病和肥胖症的新治疗靶点。