Insulin Regulation of Monoamine Signaling: Pathway to Obesity

描述（由申请人提供）：现代饮食习惯已经失控：尽管我们知道得更好，但我们还是摄入了太多的卡路里、太多的脂肪和太多的糖。在此，我们提出了一个想法，可以解释我们在对抗肥胖方面缺乏成功，并有望改变我们解决这一问题的方法。这一假设源于人们对中脑多巴胺信号在食物摄入复杂方面的重要性的认识，以及胰岛素直接调节多巴胺信号和奖励的开创性观察。我们认为，中脑纹状体等区域完整的胰岛素信号支持多巴胺能信号和正常的食物奖励，这是在卡路里稀缺时的适应性。在我们现代的，能量密集的食物环境中，奖励驱使着糟糕的饮食决定。奖励驱动的过度食用致肥食物会迅速导致神经元胰岛素抵抗和纹状体多巴胺信号受损。这一阶段形成了“低多巴胺能奖励缺乏症”，多巴胺张力降低导致肥胖食物的摄入增加，以在多巴胺张力降低的情况下达到正常的奖励水平。我们的首要假设是，对食物的奖励引发了中脑胰岛素抵抗，从而维持了食物摄入量的增加，喂养和行为的不适应，最终导致肥胖。确定胰岛素微调控制下丘脑和中脑奖励中心进食的分子机制，以及确定肥胖中该系统失调的机制，将产生巨大的见解。为了实现这一目标，我们将使用饮食引起的肥胖啮齿动物模型，其中摄食行为会发生巨大变化。在这个模型中，a)我们将首次量化中脑和下丘脑胰岛素作用和中脑DA信号随时间的详细病理改变，b)我们将使用一系列尖端工具定义中脑和下丘脑这些改变所涉及的分子机制，c)随着模型的完善和调节节点的确定，拯救病理改变，证明这项工作的治疗潜力。并确定与肥胖发病机制有关的特定大脑区域。我们将在体内启动这些研究，然后在离体制剂中模拟体内研究结果，从而提炼出喂养调节的各个方面，这是一个涉及认知和奖励的复杂过程。最后，小鼠模型中的遗传工具将阐明胰岛素和多巴胺信号在特定神经元群（如多巴胺神经元）肥胖发展中的作用。研究胰岛素和多巴胺能行为之间的这种联系将为理解肥胖和多巴胺相关合并症的可能共享机制奠定基础；认知功能障碍，双相情感障碍，精神分裂症和注意力缺陷障碍。

DESCRIPTION (provided by applicant): Modern dietary practices are out of control: despite knowing better, we consume too many calories, too much fat, and too much sugar. Herein we propose an idea that may explain our lack of success in combating obesity and that promises to transform our approach to this problem. This hypothesis arises from the recognized importance of midbrain dopamine signaling in complex aspects of food intake AND the seminal observation that insulin directly regulates dopamine signaling and reward. We propose that intact insulin signaling in midbrain areas such as striatum supports dopaminergic signaling and normal reward for food, which is adaptive when calories are scarce. In our modern, energy-dense food environment, reward drives poor dietary decisions. Reward-driven over-consumption of obesogenic foods quickly leads to neuronal insulin resistance and impaired dopamine signaling in striatum. In this stage the "hypodopaminergic reward deficiency syndrome" is established, in which decreased dopamine tone results in increased intake of obesogenic foods to achieve a normal level of reward in the setting of decreased dopamine tone. Our overarching hypothesis is that reward for food triggers midbrain insulin resistance, which sustains increased food intake, maladaptive feeding and behaviors, and as a consequence, obesity. Identification of the molecular mechanisms by which insulin fine-tunes control of feeding in the hypothalamus and reward centers in midbrain and identification of the mechanisms by which dysregulation of this system develops in obesity will yield tremendous insight. To achieve this goal, we will use a rodent model of diet-induced obesity in which dramatic changes in feeding behaviors occur. In this model a) for the first time we will quantify detailed pathological alterations in midbrain and hypothalamic insulin action and midbrain DA signaling over time, b) we will define the molecular mechanisms involved in these alterations in midbrain and hypothalamus using an array of cutting-edge tools, and c) as the model is refined and regulatory nodes identified, rescue the pathological alterations, proving the therapeutic potential of this work, and defining specific brain regions involved in obesity pathogenesis. We will initiate these studies in vivo, and will then model in vivo findings in ex vivo preparations, thereby distilling individual aspects of feeding regulation, a complex process involving cognition and reward. Finally, genetic tools in mouse models will illuminate the roles of insulin and dopamine signaling in the development of obesity in specific neuronal populations (e.g. dopamine neurons). Investigating this link between insulin and dopaminergic behavior will lay the foundation for understanding possible shared mechanisms of obesity and dopamine-related co- morbidities; cognitive dysfunction, bipolar disorder, schizophrenia, and attention-deficit disorder.