Hypothalamic Microglia as Dual Hubs Orchestrating Local and Systemic Homeostasis in the Periphery-Central-Periphery...

The hypothalamus orchestrates systemic homeostasis by integrating neuroendocrine, autonomic, and immune-metabolic functions. In this review, we synthesize evidence that hypothalamic microglia act as dual hubs along a periphery-central-periphery axis across three domains: Peripheral effects: Microglia decode circulating cues and relay them to hypothalamic circuits, thereby modulating autonomic tone and endocrine pathways that impact immune-metabolic balance. Central mechanisms: Microglia sense and shape hypothalamic neural circuits via cytokine-neurotransmitter crosstalk, synaptic remodeling, and glial-neuronal signaling that tune neuroendocrine output. Translational links: Microglial states associate with biomarkers and clinical phenotypes in metabolic and inflammatory disorders, suggesting therapeutic entry points. Drawing on the literature from the last 20 years, we highlight convergent mechanisms, unresolved heterogeneity across models, and priorities for causal dissection and target validation. This framework clarifies how hypothalamic microglia coordinate local CNS processes with systemic physiology in health and disease.