Interleukin-17A Links Obesity-Induced Inflammation to Behavioral Disorders and Autonomic Imbalance.

Abstract

Obesity is increasingly recognized as a chronic inflammatory condition, often driven by prolonged high-fat diet (HFD) consumption. Beyond causing metabolic dysregulation, obesity can disrupt immune-brain communication, contributing to the development of emotional disorders. During the early stages of HFD exposure, proinflammatory cytokines such as interleukin-1β (IL-1β), Tumor necrosis factor-alpha (TNF-α), and IL-6 are markedly elevated, but their levels typically return to baseline over time. Despite this normalization, persistent neuroinflammation and gliosis are observed, suggesting that adaptive immune mediators may play a role in chronic neuropathology. In our study using male C57BL/6 mice, 12 and 16 weeks of HFD-induced obesity increased plasma IL-17A levels, a key cytokine produced by CD4+ T helper 17 (Th17) cells, and upregulated IL-17A mRNA expression in the hypothalamus. Peripheral administration of recombinant IL-17A via intraperitoneal (i.p.) injection every 2 days for 4 weeks induced depressive and anxiety-like behaviors, accompanied by enhanced microgliosis in emotion-related brain regions and infiltration of CD4+/IL-17A+ cells in the meninges. Peripheral IL-17A administration also reduced heart rate variability (HRV), accompanied by altered HRV-derived indices, suggesting disruption of autonomic nervous system (ANS) regulation. Systemic administration of plasma derived from mice with 12-week HFD-induced obesity (OB plasma) evoked depressive and anxiety-like phenotypes, as well as ANS dysfunction. Neutralizing anti-IL-17A in the OB plasma effectively blocked these emotional and physiological impairments induced by OB plasma administration. Thus, our findings identify IL-17A as a critical mediator linking metabolic dysfunction, neuroinflammation, and emotional disorders, highlighting its potential as a therapeutic target for obesity-associated depression and anxiety.