Central Mechanisms Regulating Macronutrient Intake

肥胖症和糖尿病是影响生活质量的主要公共卫生问题，也具有很高的社会和 经济成本。根据CDC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，肥胖已达到流行病的程度， 60%的美国人超重或肥胖。因此，有严重的需求， 开发治疗肥胖和糖尿病的新疗法。成纤维细胞生长因子21（FGF 21）是一种 在许多肥胖动物模型和人类中，内分泌激素改善代谢功能障碍。 延长施用FGF 21导致啮齿动物体重减轻，并且施用FGF 21类似物导致啮齿动物体重减轻。 肥胖的人增加体重减轻并改善代谢概况。最近，我们发现FGF21 在生理上和生理上抑制碳水化合物的摄入和甜味偏好。 重要的是，我们和其他人已经发现，FGF 21的许多有益作用是通过其自身的调节作用介导的。 对中枢神经系统的作用。然而，FGF 21在脑和神经元中的作用机制是不明确的。 这些影响的目标尚未确定。这项提案的总体目标是确定神经 调节FGF 21介导的碳水化合物摄入抑制的回路。该补助金的目的是：1） 确定负责FGF21介导的碳水化合物摄入抑制的直接神经元靶点， 体内，2）确定催产素信号传导在FGF 21对简单糖摄入的抑制作用中的作用，以及3） 确定FGF 21对中脑边缘多巴胺系统和进食行为的调节的作用。到 为了实现这些目标，我们已经产生了新的动物模型和工具来检查这些实验。 目标。这些研究将为调节全身葡萄糖提供新的基本见解 通过外周内分泌信号作用于中枢神经系统来维持体内平衡和食物相关的奖赏。在 此外，这些研究可能会发现治疗糖尿病和肥胖症的新的治疗靶点。

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.