Extrahypothalamic PPARs and compulsive food intake

下丘脑外 PPAR 和强迫性食物摄入

基本信息

批准号：
9746543
负责人：
ERIC P ZORRILLA
金额：
$ 29.03万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9746543
关键词：
Addictive Behavior Address Affect Affinity Agonist Alcohol consumption Alcohol or Other Drugs use Anatomy Animal Model Anxiety Attention Behavior Behavioral Binge Eating Binge eating disorder Biology Blood - brain barrier anatomy Brain Brain region Cannabinoids Chronic Corpus striatum structure Data Defect Diet Dominant-Negative Mutation Dopamine Dorsal Drug Modelings Drug abuse Eating Eating Disorders Ethanol Etiology Exercise Extinction (Psychology)Food GPR119 receptor Genes Genetic Homeostasis Human Hyperphagia Infusion procedures Intervention Knowledge Laboratory Study Lead Ligand Binding Ligands Lipids Measures Metabolic Modeling Molecular Mus Mutant Strains Mice Neurobiology Neurons Obesity Overweight PPAR alpha PPAR delta PPAR gamma PPAR-beta Palate Pathway interactions Pattern Periodicity Peripheral Peroxisome Proliferator-Activated Receptors Pharmacology Phenotype Placentation Public Health Regulation Rewards Rodent Role Schedule Self Administration Signal Transduction Site Skeletal Muscle Specificity Substance Use Disorder Sucrose System Testing Therapeutic Transactivation Transgenic Organisms Translating United States Whole Organism Withdrawal Woman addiction alcohol use disorder base behavior measurement cell growth regulation cell type comorbidity conditional knockout delta receptors innovation insight mimetics molecular subtypes mouse model multidisciplinary nerve stem cell nestin protein novel obesity treatment outcome forecast receptor therapeutic target tool transcription factor translational approach

项目摘要

Abstract Many people with obesity or binge eating show addiction-like behavioral changes that can be modeled in rodents with intermittent, extended access to palatable food. New neurobiological understanding of and therapeutic targets for compulsive eating are needed. PPARs are lipid-sensing transcription factors encoded by 3 genes (PPARα, PPARγ, PPARβ/δ) that were identified for their roles in peripheral regulation of fuel homeostasis. PPARα and PPARγ also have received intense attention for their anti-addiction-like actions. Yet, the role of brain PPARδ receptors in the control of compulsive eating, which has overlapping striatal substrates with alcohol and substance use disorders, is entirely unknown. Here, we test the overarching hypothesis that brain peroxisome proliferator-activated receptors-delta subtype (PPARδ) inhibit addiction-like, aspects of eating. With a novel blood-brain barrier-penetrant selective PPARδ agonist (KD3010) and cre/lox tools to manipulate PPARδ function now available, the proposed studies address these gaps in the field and may yield new translational approaches and insight into the biology of brain PPARδ and their role in the control of compulsive eating and potentially other addiction phenotypes. Using an innovative, drug abuse-like mouse model, based on intermittent, extended access to highly palatable food, Aim 1 tests the roles of central vs. peripheral PPARδ receptors in compulsive-like food intake. Guided by preliminary data, Aim 2 test the functional role of PPARδ receptors in dopamine Drd2/Adora2a- vs Drd1- expressing medium spiny neurons. The resulting data and novel genetic and translationally-relevant pharmacological tools for this understudied PPARδ isotype will lay the groundwork for cell type- and anatomically-specific mechanistic studies and may lead to interventions for people affected by compulsive eating and potentially other forms of addiction.

抽象的许多肥胖或暴饮暴食的人表现出类似成瘾的行为变化，可以用以下模型进行建模：啮齿类动物间歇性地、长期地获取美味食物。需要针对强迫性饮食的治疗靶标，PPAR 是编码的脂质感应转录因子。由 3 个基因（PPARα、PPARγ、PPARβ/δ）决定，这些基因在燃料的外周调节中发挥作用 PPARα 和 PPARγ 也因其抗成瘾作用而受到广泛关注。大脑 PPARδ 受体在控制强迫性饮食中的作用，其具有重叠的纹状体底物与酒精和物质使用障碍有关，这是完全未知的。在这里，我们测试了一个总体假设：脑过氧化物酶体增殖物激活受体-δ亚型（PPARδ）抑制成瘾样，方面使用新型血脑屏障渗透性选择性 PPARδ 激动剂 (KD3010) 和 cre/lox 工具来控制饮食。操纵 PPARδ 功能现已可用，拟议的研究解决了该领域的这些空白，并可能产生对大脑 PPARδ 生物学及其在控制中的作用的新转化方法和见解使用创新的、类似药物滥用的小鼠来治疗强迫性饮食和潜在的其他成瘾表型。模型，基于间歇性、延长获得高度适口食物的机会，目标 1 测试中枢神经元与副神经元的作用。在初步数据的指导下，目标 2 测试了强迫性食物摄入中的外周 PPARδ 受体。 PPARδ 受体在表达多巴胺 Drd2/Adora2a 与 Drd1 的中型多棘神经元中的功能作用。由此产生的数据以及新的遗传和翻译相关药理学工具 PPARδ 同种型将为细胞类型和解剖特异性机制研究奠定基础，并可能导致对受强迫性饮食和潜在其他形式成瘾影响的人进行干预。