Extrahypothalamic PPARs and compulsive food intake

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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.