Hypothalamic neurovascular and extracellular matrix remodeling: Cellular niche orchestration of immune-metabolic adaptation to nutritional stress

Under normal physiological conditions, hypothalamic resident immune cells interact with neurons and other non-neuronal cells to maintain tissue homeostasis. Accumulated evidence from studies with rodents shows that excessive intake of saturated fatty acids triggers hypothalamic neuroinflammation, innate and adaptive immune activation, and chemotaxis of peripheral immune cells toward the hypothalamus. The functional consequences of this immune activation are not uniformly detrimental, as specific immune subsets can instead support metabolic resilience. Beyond this functional heterogeneity, the structural mechanisms underlying immune cell recruitment within the arcuate nucleus (ARC) and median eminence (ME), particularly extracellular matrix (ECM) and neurovascular remodeling, remain poorly defined. To address this gap, this review integrates established mechanisms from other central nervous system compartments with recent hypothalamic findings, proposing a framework for how structural changes, including microgliosis, tanycyte barrier breakdown, and ECM and neurovascular remodeling, orchestrate immune-metabolic adaptations within the ARC and ME under nutritional stress. We further provide an overview of the hypothalamic immune landscape and describe how microglia, perivascular macrophages, and tanycytes, are involved with this hypothalamic niche remodeling.