Extrahypothalamic PPARs and compulsive food intake

摘要 许多肥胖或暴饮暴食的人表现出类似成瘾的行为变化， 啮齿类动物间歇性的，延长获得可口的食物。神经生物学对和的新认识 需要针对强迫性进食的治疗目标。PPARs是编码的脂质敏感转录因子 通过3个基因（PPARα，PPARγ，PPARβ/δ），它们被鉴定为在外周调节燃料中的作用， 体内平衡PPARα和PPARγ也因其抗成瘾作用而受到广泛关注。然而， 大脑中的过氧化物酶体增殖物激活受体δ受体在控制强迫性进食中的作用，它具有重叠的纹状体底物 与酒精和物质使用障碍，是完全未知的。在这里，我们测试的首要假设， 脑过氧化物酶体增殖物激活受体-δ亚型（PPARδ）抑制成瘾样， 吃用一种新的血脑屏障选择性过氧化物酶体增殖物激活受体δ激动剂（KD 3010）和cre/lox工具， 操纵现在可用的PPARδ功能，拟议的研究解决了该领域的这些空白，并可能产生 新的翻译方法和深入了解大脑过氧化物酶体增殖物激活受体δ的生物学及其在控制 强迫性进食和潜在的其他成瘾表型。使用一种创新的，类似药物滥用的老鼠 模型，基于间歇性的，扩展获得高度可口的食物，目标1测试的作用，中央与 外周PPARδ受体在强迫性食物摄入中的作用在初步数据的指导下，目标2测试了 PPARδ受体在多巴胺Drd 2/Adora 2a- vs Drd 1-表达的中型多棘神经元中的功能作用。 由此产生的数据和新的遗传和预防相关的药理学工具， 过氧化物酶体增殖物激活受体δ同种型将为细胞类型和解剖学特异性机制研究奠定基础， 导致对受强迫性进食和潜在其他形式成瘾影响的人进行干预。

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.