Extrahypothalamic PPARs and compulsive food intake

摘要 许多肥胖或暴饮暴食的人表现出类似于成瘾的行为变化，这些变化可以在 啮齿动物有间歇性的，延长了获取美味食物的机会。对AND的神经生物学新认识 强迫性进食的治疗目标是必要的。PPAR是编码的脂质感应转录因子 通过3个基因(PPARα、PPARγ、PPARβ/δ)鉴定它们在燃料外周调节中的作用 动态平衡。PPARα和PPARγ也因其抗成瘾作用而受到高度关注。然而， 脑内PPARδ受体在控制强迫性进食中的作用 与酒精和药物使用障碍，是完全未知的。在这里，我们测试了压倒一切的假设 脑内过氧化物酶体增殖物激活受体--δ亚型抑制成瘾样作用 吃东西。使用一种新的血脑屏障穿透性选择性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空白，并可能产生 新的翻译方法和对脑PPARδ生物学的洞察及其在控制脑血管疾病中的作用 强迫性进食和潜在的其他成瘾表型。使用一种创新的、类似药物滥用的鼠标 模型，基于间歇性、延长获得高度可口的食物，目标1测试中央与 强迫型食物摄入中的外周PPARδ受体。在初步数据的指导下，目标2测试了 PPARδ受体在多巴胺drd2/adora2a-vsDRd1表达的中等刺神经元中的功能作用 由此产生的数据和新的遗传学和翻译相关的药理学工具尚未得到研究 PPARδ亚型将为细胞类型和解剖学的特定机制研究奠定基础，并可能 导致对受强迫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.