Central Mechanisms Regulating Macronutrient Intake

肥胖和糖尿病是影响生活质量的主要公共卫生问题，也有很高的社会和 经济成本。根据美国疾病控制与预防中心的数据，现在大约10%的美国成年人患有糖尿病，33%的人患有糖尿病 预计到2050年将患上糖尿病。与此同时，肥胖症已经达到流行的程度，超过 60%的美国人口超重或肥胖。因此，有一个严重的需求， 开发抗击肥胖和糖尿病的新疗法。成纤维细胞生长因子21(FGF21)是一种 改善一些肥胖动物模型和人类代谢功能障碍的内分泌激素。 延长给予FGF21可使啮齿类动物体重减轻，而给予FGF21类似物可使其体重减轻 肥胖的人会减轻体重，改善新陈代谢状况。最近，我们发现FGF21 具有抑制碳水化合物摄取和甜味偏好的生理和药理作用。 重要的是，我们和其他人已经发现，FGF21的许多有益影响是通过其 对中枢神经系统的作用。然而，FGF21在脑和神经元中的作用机制 这些效应的目标(S)尚未确定。这项提议的总体目标是识别神经 回路(S)调节成纤维细胞生长因子21介导的碳水化合物摄入抑制。这笔赠款的目标是1) 确定FGF21介导的碳水化合物摄入抑制的直接神经元靶点 体内，2)确定催产素信号在成纤维细胞生长因子21‘S抑制单纯糖摄入量中的作用；3) 确定FGF21对中脑边缘多巴胺系统和摄食行为的调节作用。至 为了实现这些目标，我们产生了新的动物模型和工具来检验这些实验 目标。这些研究将为全身葡萄糖的调节提供新的基本见解。 通过外周内分泌信号作用于中枢神经系统的动态平衡和与食物相关的奖励。在……里面 此外，这些研究可能确定治疗糖尿病和肥胖症的新靶点。

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.