Fat Regulates Inflammatory Arthritis

Abstract

Obesity is associated with inflammatory arthritis (IA) but the mechanisms linking adipose tissue to joint inflammation are enigmatic. We explored this issue by selectively expressing diphtheria toxin in adipose tissue yielding “fat-free” (FF) mice completely lacking white and brown fat. FF mice exhibit systemic neutrophilia and elevated serum acute phase proteins, suggesting predisposition to severe IA. Surprisingly, however, FF mice are completely resistant to K/BxN serum-induced IA, maintaining normal ankle and paw thickness and no evidence of enhanced osteoclastogenesis or periarticular bone destruction. Despite their robust systemic basal neutrophilia, no neutrophil infiltration into joints of FF mice occurs when challenged with K/BxN serum. Absence of adiponectin, leptin or both has no effect on joint disease but deletion of the adipokine, adipsin (complement factor D) completely prevents serum-induced IA. Confirming fat-ex-pressed adipsin modulates the disorder, transplantation of WT adipose tissue into FF mice is sufficient to restore susceptibility to IA, whereas recipients of adipsin-deficient fat remain resistant. Our studies provide the first direct evi-dence that adipose tissue regulates development of IA and reveal a previously unrecognized pathway in which adipocytes modify neutrophil responses in distant tissues by producing adipsin.