Adipokines and cell metabolism in early rheumatoid arthritis

Abstract

This thesis aimed to investigate the role of adipokines as adiponectin, leptin, and resistin, as well as cell metabolism in rheumatoid arthritis (RA). We assessed whether these adipokines are associated with inflammation and disease activity, as well as chemokines in early RA. In addition, we determined the role of these adipokines as predictors of treatment response in participants with early RA. Furthermore, we tested whether these adipokines have a causal effect on RA risk. Finally, we aimed to identify metabolites characterising the metabolic fingerprint of RA fibroblast-like synoviocytes (FLS) and to elucidate the metabolic and bioenergetic alterations in RA FLS. In Paper I we measured adiponectin, leptin, and resistin, as well as chemokines in plasma from participants with early RA, showing that only adiponectin associated with inflammation markers and chemokines. In Paper II we used publicly available data from genome-wide association studies to perform a Mendelian randomisation analysis, finding that adiponectin, leptin, and resistin do not have a causal effect on the risk to develop RA. In Paper III we measured the levels of the three adipokines in plasma of participants of the NORD-STAR study followed-up for up to 48 weeks; neither of the adipokines could predict response to treatment regardless of treatment arm. Finally, in Paper IV we performed a metabolomics analysis of RA vs non-inflamed (NI) FLS followed by cellular assays, showing a distinct metabolic fingerprint in RA FLS characterised by acylcarnitine enrichment. Further assays noted that acylcarnitine accumulation is unlikely to be the result of differential carnitine-related protein expression or carnitine and fatty acid uptake, while Seahorse assays showed that RA FLS have energetic impairment. In conclusion, our findings indicate that, although adiponectin, leptin, and resistin levels are associated with inflammation markers and chemokines in people with early RA, they are not causally associated with the risk to develop RA and are not good biomarkers of response to anti-rheumatic treatment in early RA. This thesis also shows that acylcarnitine accumulation is a characteristic of RA FLS metabolic fingerprint and is likely associated with bioenergetic impairment in these cells.