“The macrophages begin to release the inflammatory cytokines and the T cells come in and make Interferon γ,” says Dr. Brenner. “Now, you have gone from the anti-inflammatory state with IL-4, IL-10 and IL-13 being predominant, to a more pro-inflammatory one with higher production of TNF and IL-1 and IL-6.”
Models for Possible Systemic Effects
For these factors to have any relevance in rheumatic disease, they must have a systemic effect outside of the fat cells themselves. It has been shown that elevated serum levels of these pro-inflammatory cytokines are seen in obese people. Although there is still little direct evidence for how obesity affects inflammatory illnesses, such as RA and others, mouse models strongly suggest that inflammation does have a role to play in type 2 diabetes and could be a general model for discussions in humans.
“Type 2 diabetes is not a disease in which there is too little insulin, but rather one of insulin resistance where there is interference with insulin-stimulated glucose entry into the cells,” says Dr. Brenner. “TNF, for example, interferes with insulin receptor signaling through inappropriate phosphorylation of one of its substrates.”
Similar Profiles
There are some interesting, if not yet proved, similarities between the cytokine profiles seen in insulin resistance and rheumatic diseases. In obesity, the M1 inflammatory macrophage becomes the dominant cell of this type.3
“This is similar to what you see in the synovium in RA,” says Dr. Brenner. “You find these macrophages making TNF and IL-1, which leads to the activation of synovial fibroblasts. This results in the recruitment of leukocytes that drive a cycle of increased inflammation that activates fibroblasts and drives osteoclastogenesis. The same cytokines that drive insulin resistance in obesity are those that play a role in changes in the synovium, namely TNF, IL-β and IL-6.”
The lack of Tregs in obesity is another component of a possible link between RA and obesity. Tregs are important because they fulfill an anti-inflammatory role, stopping inflammation promoting cells from other T cells, B cells or macrophages.4
“In obesity, the Treg cells either decrease in number or functionality, which is also seen in RA,” says Dr. Brenner. “Down-regulation results in less suppression of inflammation. Your system not only steps on the gas, but also takes its foot off the brake.”
The cell types seen in insulin resistance from obesity in mice are basically the same in both insulin resistance and RA in humans and how they work in this context is well established. What is open to conjecture is whether this increase in pro-inflammatory cytokines in fat is the reason that we see higher levels of RA in those who are obese and why they have a harder time treating it.
How Does This Fit with RA?
The question then becomes how this might fit in with RA and other rheumatic diseases. Dr. Brenner thinks the higher levels of cytokines may serve to prime the synovium for inflammation or push the body over a minimum threshold that triggers the disease process. This might be an explanation for both the increasing incidence of RA being seen in younger patients and some less responsiveness to medications seen in some obese patients.
