Sex-dependent hypothalamic microinflammation and microglial polarization: The role of JNK in high-fat diet-induced insulin resistance

Obesity and its associated metabolic disorders, including insulin resistance and type 2 diabetes, are major global health challenges. Early hypothalamic microinflammation is emerging as a key contributor to the onset of metabolic dysfunction, but its temporal dynamics, underlying mechanisms, and sex-specific differences remain unclear. Here, we examined the effects of short-term high-fat diet (HFD) exposure on hypothalamic microinflammation, glial activation, and insulin signaling in male and female mice. Males rapidly developed hypothalamic microinflammation, characterized by increased pro-inflammatory cytokines, reactive gliosis, and impaired insulin signaling, whereas females did not show these alterations. Interestingly, we also observed a sex-specific pattern in microglial M2 polarization: females maintained a sustained M2 response throughout the experimental period, while males exhibited only a transient peak that declined in the following days. These sex-specific differences in microglial dynamics and polarization may be linked to the c-Jun N-terminal kinase pathway, a classical mediator of inflammatory signaling. To further explore this, we analyzed mice lacking JNK3, the CNS-enriched isoform of JNK. Loss of JNK3 disrupted early microglial polarization, abolished the transient M2 response, and predisposed males to enhanced gliosis and partial hypothalamic insulin resistance, while females retained partial resilience. These findings indicate that JNK3 contributes to the regulation of microglial dynamics and polarization in response to metabolic stress. Overall, our study highlights a sex-dependent role of microglia and JNK in shaping early hypothalamic microinflammation and central insulin sensitivity, providing potential targets for intervention in obesity-associated metabolic disease.