Hypothalamic neuroimmune remodeling as an immunometabolic bridge between childhood obesity and earlier pubertal onset

While the link between childhood obesity and central precocious puberty (CPP) is well documented, the immune-mediated mechanisms that may precipitate earlier pubertal onset remain incompletely understood. This review proposes hypothalamic neuroimmune remodeling as a candidate immunometabolic bridge through which chronic low-grade peripheral inflammation may influence the timing of hypothalamic-pituitary-gonadal (HPG) axis activation. In obesity, systemic immune activation is primarily by adipose tissue macrophage infiltration, lipotoxic signaling, and gut dysbiosis. Peripheral inflammatory signals may reach the central nervous system through the arcuate nucleus-median eminence complex, disruption of the blood-brain barrier, and immune-mediated gut-brain pathways. Within the hypothalamus, these signals may elicit local neuroimmune responses. Glial cells, particularly microglia, astrocytes, and tanycytes, undergo inflammatory activation and release cytokines and lipid mediators, including IL-1β, TNF-α, and prostaglandin E2. This localized neuroimmune response may alter the excitatory milieu and synaptic connectivity of the kisspeptin-GnRH network, thereby lowering the threshold for HPG axis activation. This review systematically synthesizes current evidence on this immune-endocrine crosstalk and describes how peripheral immune signals may remodel the hypothalamic microenvironment and alter pubertal timing. We further discuss the translational potential of targeting specific neuroimmune pathways for biomarker discovery and the development of novel immunomodulatory interventions for CPP. Although neuroimmune remodeling represents a plausible mechanism underlying obesity-associated pubertal advancement, its causal role requires further validation through targeted mechanistic studies and longitudinal immunophenotyping.