Amylin Modulates Food Reward

 描述（由申请人提供）：拟议的研究重点是神经肽胰淀素及其在控制可口的食物摄入量和体重中的作用，通过在中脑边缘奖励系统的腹侧被盖区（VTA）的行动。FDA批准的用于治疗II型糖尿病的胰淀素类似物产生血糖调节的改善，并且另外在人和动物模型中产生食物摄入和体重的有意义的减少。虽然文献主要集中在尾侧脑干的最后区（AP）作为介导胰淀素信号传导的厌食作用的主要部位，但重要的是要注意胰淀素受体也在与奖励和认知过程相关的脑区域中表达[例如VTA，丘脑核（NAc）]，并且几乎没有研究来检查它们对能量平衡控制的贡献。事实上，用胰淀素类似物治疗的人报告改善了对进食的控制，并降低了45%的暴饮暴食风险。此外，用胰淀素受体激动剂治疗的人比不太可口的食物更能减少他们对高度可口的食物的摄入。鉴于导致肥胖的过量食物摄入部分是由暴露于与可口食物相关的外部刺激所驱动的，因此研究神经生物学系统以减少响应于食物相关刺激的过度食物寻求和消耗是至关重要的。考虑到联合药物治疗比单一药物治疗更有希望用于肥胖治疗，评估胰淀素与其他生理系统相互作用以产生增加的食物摄入减少的潜力也是至关重要的。事实上，新兴的基础科学和临床证据表明，胰淀素和脂肪组织来源的激素瘦素的组合信号可以导致对食物摄入的增强（潜在协同）抑制。VTA中的瘦素或胰淀素的内源性信号传导对于食物摄入的正常控制是必要的，因此突出了VTA作为介导胰淀素-瘦素相互作用的潜在神经位点。本实验将利用联合收割机结合行为、分子、电生理、电化学、神经药理学、遗传和转基因技术的新方法来研究：[1]在过度进食中介导内源性腹侧被盖胰淀素受体信号传导作用的神经元和行为机制; [2]腹侧被盖胰淀素受体信号传导是否调节NAc多巴胺和NAc神经活动以响应食物提示;[3] VTA加工是否介导胰淀素和瘦素信号传导之间的食物摄入减少相互作用。这项研究将为开发更有效的淀粉样蛋白介导的肥胖治疗方案提供一个新的框架。

 DESCRIPTION (provided by applicant): The proposed research focuses on the neuropeptide amylin and its role in controlling for palatable food intake and body weight through action in the ventral tegmental area (VTA) of the mesolimbic reward system. FDA-approved amylin analogs for the treatment of Type II Diabetes Mellitus produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. While the literature has largely focused on the area postrema (AP) of the caudal brainstem as the primary site mediating the anorectic effects of amylin signaling, it is important to note that amylin receptors are also expressed in brain regions associated with reward and cognitive processes [e.g. VTA, nucleus accumbens (NAc)] and little-to-no investigation has been done to examine their contribution to energy balance control. Indeed, humans treated with an amylin analog report improved perceived control of eating and a 45% reduced risk of binge eating. Moreover, humans treated with amylin receptor agonists reduce their intake of highly palatable food more so than less-palatable food. Given that the excessive food intake contributing to obesity is driven, in part, by exposure to external stimuli associated with palatable food, it is of critical importance to investigate neurobiological systems that function to reduce excessive food seeking and consumption in response to food-related stimuli. It is also critical to evaluate the potential for amylin to interact with other physiological systes to produce an augmented reduction in food intake given that combination drug therapy holds greater promise than monotherapy for obesity treatment. Indeed, emerging basic science and clinical evidence shows that combined signaling by amylin and the adipose-tissue derived hormone leptin can lead to enhanced (potentially synergistic) suppression of food intake. Endogenous signaling by either leptin or amylin in the VTA is necessary for the normal control of food intake, thus highlighting the VTA as a potential neural locus mediating the amylin-leptin interaction. Experiments in this proposal will utilize novel approaches that combine behavioral, molecular, electrophysiological, electrochemical, neuropharmacological, genetic, and transgenic techniques to examine: [1] the neuronal and behavioral mechanisms mediating the role of endogenous VTA amylin receptor signaling in excessive feeding; [2] whether VTA amylin receptor signaling modulates NAc dopamine and NAc neural activity in response to food cues; [3] whether VTA processing mediates the food intake reducing interaction between amylin and leptin signaling. The research proposed will provide a novel framework for the development of more effective amylin-mediated treatment options for obesity.