Unraveling the homeostatic and hedonic circuits underlying feeding behavior and obesity

揭示进食行为和肥胖背后的稳态和享乐回路

• 批准号: 10662504
• 负责人: Amber L Alhadeff
• 金额: $ 44.95万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662504
• 关键词: ART protein; Adult; Anatomy; Biological Markers; Body Weight decreased; Brain; Brain region; Corpus striatum structure; Development; Diet; Dopamine; Dorsal; Eating; Fatty acid glycerol esters; Feeding behaviors; Food; Future; Genetic; Hunger; Hyperphagia; Hypothalamic structure; Individual; Individual Differences; Intake; Lateral; Link; Mediating; Midbrain structure; Modernization; Molecular Target; Monitor; Mus; Neurons; Neurotransmitters; Nutrient; Obesity; Pathologic; Pattern; Persons; Pilot Projects; Predisposition; Prevalence; Prevention strategy; Public Health; Rewards; Rodent Model; Role; Signal Transduction; Signaling Protein; Site; System; Testing; Thinness; Time; United States; Ventral Striatum; Weight Gain; Work; cell type; cellular targeting; diet-induced obesity; dopaminergic neuron; experimental study; feeding; food environment; genetic technology; hedonic; in vivo; mouse model; neural; neural circuit; neural correlate; novel strategies; obesity development; obesity prevention; obesity treatment; obesogenic; optogenetics; pharmacologic; pleasure; response; sugar; treatment strategy

PROJECT SUMMARY The striking prevalence of obesity and its associated personal and public health consequences highlights the importance of understanding why individuals overeat and gain weight. It is widely recognized that overeating results from a combination of homeostatic (i.e., nutrient need, hunger) and hedonic (i.e., pleasure, reward) drives. While these homeostatic (e.g., hypothalamic) and hedonic [e.g., midbrain dopamine (DA)] systems have been characterized as discrete drivers of food intake, there is considerable evidence that these systems overlap. For example, DA signaling in response to food is potentiated by hunger, increasing the reward value of food during times of homeostatic need. Our recent findings in rodent models revealed a neural correlate for the interaction between homeostatic and hedonic systems. Activity in hunger-sensitive, hypothalamic agouti-related protein (AgRP)-expressing neurons potentiates the DA response to food. Conversely, DA signaling enhances the homeostatic AgRP neuron response to food. What are the circuits through which AgRP and DA neurons interact in response to food? Do they help explain why some individuals are more likely to overeat and gain weight? This proposal will test the overarching hypotheses that distinct AgRP and DA neuron subpopulations mediate the interaction between homeostatic and reward signaling and that individual differences in AgRP and DA responses to food predict future weight gain. Aim I experiments will determine the AgRP neuron projection subpopulations that potentiate DA responses to food. We will leverage the anatomical organization of AgRP neurons, as well as optogenetic and chemogenetic technologies, to individually test how each AgRP projection subpopulation influences food-evoked DA signaling. Aim II experiments will determine sites of action for DA modulation of AgRP neuron activity. We will use genetic and pharmacological approaches to examine how DA projections and neurotransmitter signaling influence AgRP neuron activity. Aim III will determine how AgRP and DA activity predicts future overeating and weight gain. Taking advantage of the variability in weight gain in response to a high-fat, high-sugar diet, we will determine if individual differences in neural activity in lean mice predict future overeating and the development of obesity. Overall, these experiments take a unique approach to understanding weight gain by (1) determining the neural intersection of homeostatic and hedonic circuits that have classically been considered discrete drivers of intake and (2) identifying neural activity biomarkers to predict overeating and obesity predisposition. Ultimately, results from the proposed studies will reveal cellular and molecular targets that can be leveraged to develop obesity prevention and more effective weight loss strategies.

项目摘要 肥胖症的惊人患病率及其相关的个人和公共卫生后果突出了 理解个人为什么暴饮暴食和体重增加的重要性。广泛认识到暴饮暴食 稳态（即营养需求，饥饿）和享乐主义者（即愉悦，奖励）驱动器的结合。 这些稳态（例如，下丘脑）和享乐者[例如，中脑多巴胺（DA）]系统已经是 被认为是食物摄入的离散驱动因素，有大量证据表明这些系统重叠。为了 例如，对食物的DA信号通过饥饿增强，增加了食物的奖励价值 稳态需求的时代。我们最近在啮齿动物模型中的发现显示了相互作用的神经相关性 在体内和享乐系统之间。与饥饿敏感的下丘脑Agouti相关蛋白的活性 （AGRP）表达神经元可以增强对食物的DA反应。相反，da信令增强了 稳态AGRP神经元对食物的反应。 AGRP和DA神经元相互作用的电路是什么 回应食物？他们是否有助于解释为什么有些人更有可能暴饮暴食和增加体重？这 提案将测试不同的AGRP和DA神经元亚群的总体假设 体内稳态和奖励信号之间的相互作用以及AGRP和DA响应中的个体差异 食物预测未来的体重增加。目的I实验将确定AGRP神经元投影亚群 这种增强了对食物的反应。我们将利用AGRP神经元的解剖组织以及 光遗传学和化学遗传技术，以单独测试每个AGRP投影如何亚群 影响食物引起的DA信号传导。 AIM II实验将确定AGRP调制DA的作用部位 神经元活性。我们将使用遗传和药理学方法来研究DA预测和 神经递质信号传导影响AGRP神经元活性。 AIM III将确定AGRP和DA活动如何 预测未来暴饮暴食和体重增加。利用体重增加的变化来响应 高脂，高糖饮食，我们将确定瘦小鼠神经活动的个体差异是否预测未来 暴饮暴食和肥胖的发展。总体而言，这些实验采用独特的理解方法 通过（1）确定具有经典的稳态和享乐电路的神经交集 被认为是摄入量的离散驱动因素和（2）识别神经活动生物标志物以预测暴饮暴食和 肥胖倾向。最终，提出的研究的结果将揭示细胞和分子靶标 可以利用这种方法来发展肥胖症预防和更有效的减肥策略。