Effects of mesolimbic amylin signaling on macronutrient intake

中脑边缘胰淀素信号传导对大量营养素摄入的影响

• 批准号: 10530695
• 负责人: Elizabeth Genevieve Mietlicki-Baase
• 金额: $ 44.21万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530695
• 关键词: Acute; Address; Affect; Appetite Depressants; Area; Automobile Driving; Award; Behavioral; Behavioral Mechanisms; Body Weight; Body Weight decreased; Brain; Carbohydrates; Cell Nucleus; Cells; Central Nervous System; Chronic; Communication; Consumption; Cost of Illness; Dependovirus; Development; Diet; Dopamine; Eating; Estradiol; Estrous Cycle; Fatty acid glycerol esters; Feedback; Female; Food; Hormones; Hyperphagia; Intake; Light; Liquid substance; Literature; Macronutrients Nutrition; Mediating; Motivation; Neurons; Nucleus Accumbens; Obesity; Pancreas; Pathway interactions; Peptides; Periodicity; Persons; Pharmacotherapy; Phase; Physiological; Physiology; Population; Publishing; Rattus; Receptor Activation; Receptor Signaling; Research; Rewards; Role; Saccharin; Scanning; Sex Differences; Signal Transduction; Site; Stimulus; Sucrose; System; Testing; United States; Ventral Tegmental Area; Weight Gain; Work; amylin receptor; design; dietary; dopaminergic neuron; energy balance; feeding; insight; interest; islet amyloid polypeptide; knock-down; male; motivated behavior; neural; neuromechanism; neurotransmission; novel; obesity treatment; peptide hormone; pharmacologic; receptor expression; reduced food intake; response; treatment strategy

Project Summary/Abstract Obesity is highly prevalent in the United States, yet available treatment options remain limited. The peptide hormone amylin, which reduces food intake and body weight, is thought to be a promising potential target for novel obesity treatments. As obesity is driven in part by overconsumption of highly palatable, rewarding foods, there is growing interest in examining how feeding-relevant signals such as amylin act at reward-relevant nuclei of the brain to control food intake. The ventral tegmental area (VTA) of the mesolimbic reward system is both physiologically and pharmacologically relevant for amylin-mediated suppression of food intake, but the behavioral and physiological mechanisms by which VTA amylin promotes negative energy balance remain unresolved. This proposal is designed to evaluate mechanisms by which VTA amylin signaling suppresses intake of particular dietary macronutrients to promote negative energy balance. Studies also further investigate sex differences in VTA amylin-mediated control of feeding and body weight, with particular focus on the influence of estradiol on the effects of VTA amylin receptor activation. Specific Aim I will test mechanisms by which VTA amylin signaling modulates dopamine signaling to suppress intake of particular dietary macronutrients. First, the hypothesis that VTA amylin receptor (AmyR) activation potently suppresses phasic dopamine in the nucleus accumbens core, another key mesolimbic nucleus, in response to intraoral fat will be evaluated with fast-scan cyclic voltammetry. We will also investigate the relative contribution of orosensory versus postingestive feedback to activation of VTA AmyR-expressing dopamine neurons. Further, we will use a Cre-dependent adeno-associated virus (AAV) to knock down AmyR expression in VTA dopamine neurons, and examine how this neuronal population contributes to endogenous control of energy balance by amylin. Specific Aim II addresses a critical gap in the literature by evaluating physiological and pharmacological relevance of VTA AmyR in control of palatable food intake and body weight in females, and will test the influence of estradiol on the energy balance effects of VTA AmyR signaling. We will also evaluate how estradiol alters expression of AmyR components in the VTA, thereby providing novel mechanistic insight into central interactions of estradiol and amylin in energy balance control. These studies build upon the PI’s previous K01 and R03 awards by investigating the neural and behavioral mechanisms by which mesolimbic amylin signaling promotes negative energy balance and will address new aspects of this area of research by providing deeper insight into the mechanisms by which VTA amylin signaling controls macronutrient intake as well as sex differences in these effects. Collectively, these studies will provide information on mechanisms of action by which amylin reduces food intake and promotes weight loss, which may in turn facilitate the development of more effective pharmacotherapies for treating obesity.

项目总结/摘要 肥胖在美国非常普遍，但可用的治疗选择仍然有限。的 肽激素胰淀素可以减少食物摄入量和体重，被认为是一种有前途的潜力 用于新型肥胖症治疗的目标。由于肥胖的部分原因是过度食用美味的食物， 奖励的食物，有越来越多的兴趣，研究如何喂养相关的信号，如胰淀素的作用， 大脑中与奖赏相关的核团来控制食物摄入。中脑边缘核腹侧被盖区（VTA） 奖赏系统与淀粉样蛋白介导的食物抑制既有生理学上的关系， 摄入量，但VTA胰淀素促进负能量的行为和生理机制 平衡尚未解决。该提案旨在评估VTA胰淀素 信号传导抑制特定膳食常量营养素的摄入以促进负能量平衡。 研究还进一步调查了腹侧被盖区淀粉蛋白介导的摄食和身体控制的性别差异。 特别关注雌二醇对VTA胰淀素受体效应的影响 activation.具体目标I将测试VTA胰淀素信号调节多巴胺信号的机制 来抑制特定膳食常量营养素的摄入。首先，VTA胰淀素受体（AmyR） 激活有效地抑制了中脑边缘核核心中的阶段性多巴胺， 将用快速扫描循环伏安法评估细胞核对口内脂肪的响应。我们亦会研究 口感觉与摄食后反馈对腹侧被盖区AmyR表达激活的相对贡献 多巴胺神经元此外，我们将使用依赖Cre的腺相关病毒（AAV）敲除AmyR 表达的腹侧被盖区多巴胺神经元，并检查如何这种神经元群体有助于内源性 通过胰淀素控制能量平衡。具体目标II通过评估来解决文献中的关键差距 VTA AmyR在控制适口性食物摄入和体重中的生理学和药理学相关性 并将测试雌二醇对VTA AmyR信号传导的能量平衡效应的影响。我们 还将评估雌二醇如何改变腹侧被盖区AmyR组分的表达，从而提供新的 对雌二醇和胰淀素在能量平衡控制中的中心相互作用的机械见解。这些研究 在PI之前的K 01和R 03奖项的基础上，通过调查神经和行为机制， 中边缘胰淀素信号促进负能量平衡，并将解决这一新的方面， 通过提供更深入的了解VTA胰淀素信号控制的机制， 大量营养素摄入以及这些影响的性别差异。这些研究将提供 胰淀素减少食物摄入和促进体重减轻的作用机制的信息， 可以反过来促进治疗肥胖症的更有效药物疗法的开发。