What Fat Does to Arthritis

Among other adipokines, resistin has been found in mice as a protein involved in adipocyte differentiation. Human resistin, on the other hand, increases the secretion of proinflammatory cytokines such as TNF, IL-6, and IL‑12, activates endothelial cells and increases endothelin-1 and several adhesion molecules as well as chemokines in these cells.⁶ Visfatin/pre–B cell colony enhancing factor (PBEF) is also called Nampt because of its nicotinamide phosphoribosyltransferase (NAmPRTase) activity. This molecule is involved in the synthesis of nicotinamide adenine dinucleotide, an essential co-factor of cell metabolism; in addition, it can activate human leukocytes and induces costimulatory molecules on the cell surface. In monocytes, visfatin/PBEF can stimulate the synthesis of proinflammatory cytokines such as IL‑1, TNF, and IL-6, and protects fibroblasts and neutrophils from apoptosis.⁷

So, how do adipokines influence the course of a chronic rheumatic disease such as rheumatoid arthritis (RA)? Given that levels of adiponectin in synovial fluid and serum are high and are related to joint destruction and long-term disease, these molecules would be expected to have an important role.⁸ Although articular “fat” is also found around an inflamed joint, the truly important finding on the role of adipokines in pathogenesis of RA related to local expression of adiponectin in joint tissue, including in the lining layer, perivascular area, and in several cells in the sublining (see Figure 1, above); adiponectin expression was also found at sites of cartilage destruction, synovial angiogenesis, and inflammation.

Regarding a role in pathogenesis, adiponectin itself can boost joint-destructive RA synovial fibroblasts to full power by inducing synthesis of proinflammatory cytokines such as IL-6, a variety of chemokines, proangiogenic factors such as vascular endothelial growth factor, and matrix-degrading proteins including collagenases.^9,10 This pathway appears to be independent of the known TNF routes because TNF and IL-1 could not be induced by adiponectin in RA synovial fibroblasts. The pluripotency of adiponectin was further illustrated by a similar effect on the rest of the “damaging orchestra of cells” in the rheumatoid joint. These cells, which play both loud and out of tune, include endothelial cells, chondrocytes, and lymphocyte subpopulations.

Figure 1: Strong expression of adiponectin (in red) in the synovial lining, mesenchymal cells of the sublining, and perivascularly in a highly inflamed rheumatoid synovial tissue.

Evolving Picture of Adipokine Action

Things are never as simple or easy as they first appear, however. As shown in subsequent studies, it has become obvious that human adiponectin consists of different isoforms and that glycosylation and oligomerization, which differ between species, are very important for the resulting functional effects of adiponectin.^10,11 Because most experiments and animal models are performed using a “wild-type” mix containing different amounts of the respective isoforms, it is not yet possible to fully determine which isoforms are dominant in RA synovial tissue at sites of cartilage degradation and inflammation.