<p>Hypothalamic inflammation represents a central mechanism linking obesity to metabolic dysfunction. This process involves glial activation and persistent innate immune signaling, with Toll-like receptor 4 (TLR4) emerging as a critical interface between inflammatory pathways and impaired central insulin signaling. Irisin, a myokine released in response to physical exercise, has been shown to exert metabolic and anti-inflammatory effects in peripheral tissues, as well as neuroprotective actions in the brain. However, whether irisin directly modulates obesity-associated hypothalamic inflammation, particularly through TLR4-dependent pathways, remains unknown. Here, we investigated the effects of short-term intracerebroventricular delivery of recombinant irisin on hypothalamic inflammatory signaling in diet-induced obese mice. Central irisin administration reduced glial reactivity, downregulated components of the TLR4/MyD88 pathway, and increased the expression of anti-inflammatory cytokines in the hypothalamus. In addition, irisin restored insulin-stimulated AKT phosphorylation and selectively reduced inguinal white adipose tissue mass without affecting overall body weight. Together, these findings indicate that central irisin administration attenuates obesity-related hypothalamic inflammation and modulates central insulin signaling, supporting a role for irisin as a regulator of neuroinflammation-linked metabolic dysfunction.</p> Graphical Abstract <p>Graphical abstract created with Biorender.com under publication license (MR296VUFQG).</p> <p></p>