Chronic inflammation may impair the normal engagement of the unfolded protein response (UPR), which is activated in the presence of ER stress. However, these processes do not function normally in an inflammatory environment, such as in obesity. For example, inflammatory signals can modify the function of critical UPR molecules responsible for restoring ER function, such as the splicing of XBP1 by the protein IRE1. In one study, this process did not occur properly in mice, resulting in dysfunctional ER and activation of the JNK pathway, which plays a role in inflammation, Dr. Hotamisligil said. This vicious cycle of inflammation and ER stress also may be seen in beta cells in Type 1 diabetes. Restoring the unfolded protein response in pancreatic beta cells protects mice against diabetes.
Over a lifetime, exposure to obesity and other metabolic stresses can create a bottleneck of macrophages and other immune cells that lead to inflammation. This condition disrupts metabolism and causes further immune activity, launching an endless, vicious cycle, Dr. Hotamisligil said.
“Adipose tissue is a nasty, hostile environment and has lots of noxious cargo. Neither adipocytes nor other critical metabolic cells can operate in full capacity when there is constant immune activity. You can no longer support metabolic homeostasis in a chronic inflammatory environment.” the rheumatologist
Susan Bernstein is a freelance medical journalist based in Atlanta.