# Central Irisin Administration Attenuates Hypothalamic TLR4/MyD88-Mediated Neuroinflammatory Signaling in Diet-Induced Obese Mice

## TL;DR

Administering irisin in the brain reduces inflammation and improves insulin signaling in obese mice.

## Contribution

This study shows that central irisin administration modulates hypothalamic TLR4/MyD88-mediated inflammation in diet-induced obesity.

## Key findings

- Central irisin reduced glial reactivity and TLR4/MyD88 pathway components in the hypothalamus.
- Irisin restored insulin-stimulated AKT phosphorylation and reduced inguinal white adipose tissue mass.
- Irisin increased anti-inflammatory cytokine expression in the hypothalamus.

## Abstract

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.

Graphical abstract created with Biorender.com under publication license (MR296VUFQG).

The online version contains supplementary material available at 10.1007/s12035-026-05729-8.