Central Zika virus infection causes hypothalamic inflammation and persistent insulin resistance in adult mice

Zika virus (ZIKV) is a neurotropic flavivirus capable of infecting the adult brain, however its impact on hypothalamic function and metabolic regulation remains unclear. Here, we show that ZIKV invades the hypothalamus of immunocompetent adult mice, where it replicates and persists, leading to sustained insulin resistance. Following infection, ZIKV RNA and negative strand were detected in the hypothalamus of mice and immunostaining confirmed viral proteins in neurons, especially POMC-positive cells. At 6 dpi, ZIKV induced hypothalamic neuroinflammation, as shown by the upregulation of TNF-α, IL-6, IFN-β, and ISG-15, as well as microglial activation. These inflammatory responses were associated with impaired insulin signaling, characterized by reduced phosphorylation of IRS-1 and S6K, downregulation of insulin receptor mRNA, and decreased anorexigenic response following intracerebral insulin administration. Our data also showed that, despite viral clearance and resolution of hypothalamic inflammation at 30 dpi, reduction in insulin receptor protein levels and hypothalamic insulin resistance persisted. These findings demonstrate that ZIKV replicates in the hypothalamus of immunocompetent adult mice, leading to long-lasting disruption of central insulin signaling. Our study identifies hypothalamic insulin resistance as a novel consequence of ZIKV central nervous system invasion and suggests that viral infections may contribute to long-term metabolic dysfunction, highlighting the need to investigate persistent hypothalamic and metabolic alterations in ZIKV infection-recovered individuals.