White adipose tissue, a novel antirheumatic target: Clues from its secretory capability and adipectomy‐based therapy

Abstract Background and Purpose White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. Experimental Approach WAT status of healthy and adjuvant‐induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre‐adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre‐adipocytes. Proteins differentially expressed in WAT of healthy and AIA rats were identified by the UPLC/MS 2 method. These together with PPARγ siRNA and agonist were used to treat pre‐adipocytes in vitro. The medium was used for THP‐1 monocyte culture. Key Results Compared with healthy controls, AIA WAT was smaller but secreted more leptin, eNAMPT, MCP‐1, TNF‐α, and IL‐6. AIA rat pre‐adipocytes increased the levels of these adipokines in healthy recipients. RA patients' serum induced a similar secretion change and impaired differentiation of pre‐adipocytes. Adipectomy eased AIA‐related immune abnormalities and arthritic manifestations. Hepatokines PON1, IGFBP4, and GPIHBP1 were among the differential proteins in high levels in RA blood, and induced inflammatory secretions by pre‐adipocytes. GPIHBP1 inhibited PPARγ expression and caused differentiation impairment and inflammatory secretion by pre‐adipocytes, a similar outcome to PPARγ‐silencing. This endowed the cells with an ability to activate monocytes, which can be abrogated by rosiglitazone. Conclusion and Implications Certain hepatokines potentiate inflammatory secretions by pre‐adipocytes and expedite RA progression by inhibiting PPARγ. Targeting this signalling or abnormal WAT secretion by various approaches may reduce RA severity.