Work

Leptin/PPARγ interaction mediates obesity-driven Th17 differentiation in rheumatoid arthritis

Year: 2025

Type: article

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, with some studies suggesting that obesity may increase the risk of developing RA. However, the relationship between obesity and RA is complex, involving both epidemiological associations and, paradoxically, protective effects. The exact role of obesity in RA pathophysiology remains controversial. In this study, we investigated the impact of obesity on RA progression, focusing on the molecular mechanisms of immune regulation mediated by the adipokine leptin. We examined obese RA patients and employed high-fat diet (HFD)-induced obesity models along with leptin gene-deficient (ob) mice to explore the influence of obesity on RA progression. Our findings revealed elevated serum leptin levels in obese RA patients, which were positively correlated with disease severity. Furthermore, HFD-induced obesity exacerbated arthritis severity in collagen-induced arthritis (CIA) mice, leading to increased joint pathology and bone destruction. To further assess the role of leptin, we utilized ob mice and exogenous leptin supplementation models to investigate its effects on CIA and Th17 polarization. Our results emphasize that leptin, rather than obesity per se, plays a critical role in RA progression by interacting with peroxisome proliferator-activated receptor gamma (PPARγ), thereby promoting Th17 cell differentiation. These findings provide valuable insights into the role of leptin in RA pathogenesis and suggest that leptin may serve as a potential therapeutic target for managing RA in obese individuals. • Obesity exacerbates rheumatoid arthritis (RA) progression, with leptin as a key mediator. • Leptin, rather than obesity itself, drives RA onset and progression by influencing immune responses. • Leptin promotes Th17 cell differentiation, a crucial mechanism in RA development. • Leptin-deficient mice are protected from RA, highlighting the role of leptin in disease pathogenesis. • Leptin modulates Th17 cell differentiation and RA progression through its interaction with PPARγ.

Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

DOI: 10.1016/j.bbadis.2025.168069