Neurobiology for Lac-Phe Hypophagia

Lac-Phe 吞食不足的神经生物学

• 批准号: 10709397
• 负责人: YONG XU
• 金额: $ 63.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709397
• 关键词: Acute; Address; Animal Feed; Anti-Obesity Agents; Appetite Stimulants; Body Weight; Body Weight decreased; Brain region; CRISPR/Cas technology; Chronic; Data; Eating; Electrophysiology (science); Energy Metabolism; Exercise; FOS gene; Feeding behaviors; Frequencies; Genetic; Genetic Recombination; High Fat Diet; Hormones; Hypothalamic structure; Intervention; Lateral; Maps; Mediating; Metabolic; Metabolic Diseases; Modeling; Mus; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Obese Mice; Obesity; Output; Pathway interactions; Peptides; Permeability; Phenylalanine; Physical activity; Pilot Projects; Plasma; Population; Potassium; Regimen; Strenuous Exercise; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic plasticity; Testing; Thinness; Weight maintenance regimen; blood-brain barrier crossing; exercise training; experimental study; feeding; glucose tolerance; improved; insight; neural; neurobiological mechanism; neurochemistry; obesity risk; parabrachial nucleus; paraventricular nucleus; pharmacologic; physical inactivity; reduced food intake; response; single-cell RNA sequencing

PROJECT SUMMARY Regular physical activity is a powerful intervention that reduces obesity and confers protection against obesity-associated metabolic diseases. The mechanisms responsible are incompletely understood but are likely to extend beyond activity-associated increases in energy expenditure alone. We recently identified a lactate-derived metabolite called N-lactoyl-phenylalanine (“Lac-Phe”) as the most significantly elevated metabolite in blood plasma after an intense exercise bout. We further demonstrated that pharmacological elevation of plasma Lac-Phe to mimic exercise training can robustly suppress feeding in obese mice, and repeated Lac-Phe regimen results in chronic hypophagia, weight loss, and reduced adiposity, associated with improved glucose tolerance. While these findings raise the possibility that Lac-Phe could be used as an anti-obesity agent, the neurobiological mechanisms underlying Lac-Phe hypophagia remains unknown. Our preliminary studies identified Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus (ARH) as one direct target of Lac-Phe action and mediate its hypophagic response. One objective is to examine effects of Lac-Phe and exercise on afferent synaptic inputs to AgRP neurons, and efferent outputs from AgRP neurons to their synaptic targets. Our data also suggest that Lac-Phe inhibits orexigenic AgRP neurons via increasing an outward potassium current, namely KATP current. Thus, the second objective is to use the CRISPR-Cas9 approach to genetically disrupt the expression of KATP channel subunits in AgRP neurons, and use these models to determine the functional relevance of KATP channel in Lac-Phe-induced AgRP inhibition and hypophagia. Finally, we also observed that Lac-Phe activates neurons in four other brain regions, the lateral septum (LS), the paraventricular nucleus of the hypothalamus (PVH), the parabrachial nucleus (PBN), and the nucleus of solitary tract (NTS). Thus, we will combine the Targeted Recombination in Active Populations (TRAP) approach with electrophysiology, chemogenetics and scRNA-Seq to determine whether Lac-Phe stimulates these neurons directly or indirectly, whether these neurons functionally participate in the Lac-Phe-induced hypophagia, and what are neurochemical identities of these Lac-Phe-activated neurons. These proposed experiments will reveal the neurobiological basis for Lac-Phe hypophagia, which may identify Lac-Phe or the associated pathways as targets for weight management.

项目摘要 定期体育锻炼是一种有力的干预措施，可减少肥胖症并承认保护 肥胖相关的代谢疾病。负责的机制尚不完全理解，但很可能是 超越与活动相关的能源消耗的增加。我们最近确定了 称为N-内酰胺 - 苯基丙氨酸（“ Lac-Phe”）的乳酸酯衍生的代谢物，是最显着升高的 激烈的运动后血浆中的代谢产物。我们进一步证明了药理学 血浆lac-phe升高到模拟运动训练可以强抑制肥胖小鼠的喂养，并且 重复的LAC-PHE方案会导致慢性低下，体重减轻和肥胖降低，与 提高葡萄糖耐受性。虽然这些发现提出了可以将Lac-Phe用作的可能性 抗肥胖剂，LAC-PHE垂体下的神经生物学机制仍然未知。我们的 初步研究确定了与Agouti相关的肽（AGRP）表达神经元的神经元 下丘脑（ARH）是LAC-PHE作用的直接靶标，并介导其下降反应。一 目的是检查Lac-Phe和运动对AGRP神经元传入突触输入的影响，以及 从AGRP神经元到其突触靶标的有效输出。我们的数据还表明LAC-PHE抑制 通过增加向外钾电流（即KATP电流），甲状腺素AGRP神经元。那，第二 目的是使用CRISPR-CAS9方法在遗传上破坏Katp通道亚基的表达 AGRP神经元，并使用这些模型来确定lac-phe诱导的KATP通道的功能相关性 AGRP抑制和垂直抑制作用。最后，我们还观察到Lac-Phe激活了其他四个大脑的神经元 区域，外侧隔膜（LS），下丘脑（PVH）的室室核核心 核（PBN）和固体道（NTS）的核。那就是我们将目标重组结合在 用电生理学，化学遗传学和SCRNA-SEQ的活动种群（陷阱）方法确定 LAC-PHE是直接还是间接刺激这些神经元，这些神经元是否在功能上参与 在LAC-PHE诱导的垂体中，这些LAC-PHE激活的神经元的神经化学身份是什么。 这些提出的实验将揭示lac-Phe Hypophagia的神经生物学基础，这可以确定 LAC-PHE或相关途径作为体重管理的目标。