PPARγ Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory...

Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated nuclear receptor traditionally associated with lipid and glucose metabolism. Emerging evidence, however, identifies PPARγ as a central immunometabolic regulator in the central nervous system (CNS), coordinating mitochondrial function, neuroinflammation, synaptic plasticity, and neurovascular integrity. Beyond its classical metabolic actions, PPARγ regulates microglial activation, astrocytic inflammatory responses, oxidative stress, and mitochondrial biogenesis, thereby influencing neuronal resilience and circuit stability. This narrative review synthesizes knowledge of PPARγ structure, activation, CNS distribution, endogenous ligands, and synthetic agonists, including thiazolidinediones and selective modulators. We highlight how PPARγ controls transcriptional programs related to energy homeostasis, inflammatory signaling, including NF κB dependent pathways, and blood brain barrier function. Attention is devoted to synaptic remodeling and plasticity, positioning PPARγ as a molecular bridge between metabolic state and neuronal adaptability. We propose that PPARγ signaling dysregulation represents a convergent mechanism in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and adrenoleukodystrophy; psychiatric conditions, such as depression and anxiety; and neurooncological processes. Integrating evidence across these conditions supports PPARγ as a master regulator of neuroimmune metabolic coupling in the brain. Finally, we discuss translational challenges and opportunities, including brain penetrant, functionally selective ligands, clarification of cell type specific signaling, and expansion of rigorous clinical trials. Integrating mechanistic, preclinical, and clinical trial evidence, this review critically examines the therapeutic potential of PPARγ across neurodegenerative, psychiatric, and neurooncological CNS conditions, while identifying priorities for future therapeutic development in diverse brain disorders.