Insulin regulation of monoamine signaling: pathway to obesity

描述(由申请人提供)：现代饮食习惯失控：尽管我们知道得更多，但我们摄入了太多卡路里、太多脂肪和太多糖。在这里，我们提出了一个想法，可以解释我们在抗击肥胖方面没有取得成功的原因，并有望改变我们解决这个问题的方法。这一假说源于公认的中脑多巴胺信号在食物摄取复杂方面的重要性，以及胰岛素直接调节多巴胺信号和奖赏的开创性观察。我们认为，纹状体等中脑区域完整的胰岛素信号支持多巴胺能信号和对食物的正常奖励，当卡路里不足时，这是适应的。在我们现代的高能量食物环境中，奖励会导致糟糕的饮食决定。在奖励的驱动下，过度食用肥胖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。在这一阶段，“低多巴胺能奖赏缺乏综合征”被确立，其中多巴胺张力降低会导致肥胖食物摄入量增加，从而在多巴胺张力降低的情况下实现正常水平的奖赏。我们的主要假设是，对食物的奖励会触发中脑胰岛素抵抗，从而导致食物摄入量增加，饮食和行为不适应，从而导致肥胖。识别胰岛素微调控制下丘脑和中脑奖励中心摄食的分子机制，以及识别肥胖时这一系统失调的机制将产生巨大的洞察力。为了实现这一目标，我们将使用饮食诱导肥胖的啮齿动物模型，在该模型中，摄食行为会发生戏剧性的变化。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变化，b)我们将使用一系列尖端工具定义这些中脑和下丘脑变化所涉及的分子机制，以及c)随着模型的完善和调节节点的确定，挽救病理变化，证明这项工作的治疗潜力，并定义参与肥胖发病机制的特定脑区。我们将在体内启动这些研究，然后在体外准备中模拟体内的发现，从而提炼出摄食调节的各个方面，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体(例如多巴胺神经元)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与多巴胺相关的共病、认知功能障碍、双相情感障碍、精神分裂症和注意缺陷障碍的可能共同机制奠定基础。 公共卫生相关性：肥胖和其他与多巴胺相关的疾病，如精神分裂症、双相情感障碍和注意力缺陷障碍，是巨大的公共卫生负担。多巴胺信号已被确认为摄食行为的关键因素，胰岛素最近被证明调节多巴胺张力。这项提案将分析高脂饮食水泥引起的胰岛素和多巴胺信号的平行变化如何改变喂养行为，从而导致肥胖和相关的共病，从而允许开发新的治疗干预措施。

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. PUBLIC HEALTH RELEVANCE: Obesity and other dopamine-related pathologies such as schizophrenia, bipolar disorder, and attention-deficit disorder are a tremendous public health burden. Dopamine signaling has been identified as a key element of feeding behavior and insulin has recently been demonstrated to regulate dopamine tone. This proposal will analyze how parallel changes in insulin and dopamine signaling, induced by high-fat feeding cement changes in feeding behavior that lead to obesity and related co-morbidities and thereby allow the development of new therapeutic interventions.