Extrahypothalamic PPARs and compulsive food intake

下丘脑外 PPAR 和强迫性食物摄入

• 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
• 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

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 许多患有肥胖或bbinge饮食的人表现出类似成瘾的行为改变，可以在 啮齿动物间歇性，扩展可口的食物。对和 需要进行强迫性饮食的治疗靶标。 PPAR是编码的脂质感应转录因子 通过3个基因（PPARα，PPARγ，PPARβ/δ），这些基因在燃料的外围调节中被鉴定出来 稳态。 PPARα和PPARγ也因其抗吸气样作用而受到了极大的关注。然而， 脑PPARδ受体在控制强迫饮食中的作用，该饮食具有重叠的纹状体底物 使用酒精和药物使用障碍，完全未知。在这里，我们检验了总体假设 脑过氧化物增生剂激活受体 - delta亚型（PPARδ）抑制类似成瘾， 吃。具有新型的血脑屏障 - 验证剂选择性PPARδ激动剂（KD3010）和Cre/Lox工具 操纵PPARδ功能现已可用，拟议的研究解决了该领域的这些差距，并可能产生 新的翻译方法和对脑PPARδ生物学的见解及其在控制中的作用 强迫性饮食和潜在的其他成瘾表型。使用创新的吸毒式鼠标 基于间歇性的，扩展对高度可口食品的扩展访问的模型，AIM 1测试了中央VS的角色。 强迫性食物摄入中的外周PPARδ受体。在初步数据的指导下，AIM 2测试 PPARδ受体在多巴胺DRD2/adora2a-vs drd1-表达培养基神经元中的功能作用。 最终的数据以及新的遗传和转换的药物工具 PPARδ同种型将为细胞类型和解剖学特异性的机械研究奠定基础，可能 为受到强迫饮食和其他形式成瘾影响的人们提供干预措施。