Yang, who recently arrived from the Harvard T.H. Chan School of Public Health, conducted the study with colleagues there, including senior author Gökhan Hotamisligil, MD, PhD. The findings were published July 31 in the journal Science (http://www.sciencemag.org/content/349/6247/500.full?sid=1ca206ca-fd07-4320-aa50-7feae6c2aa05).
The team found that obesity-associated inflammation disrupts a cellular stress defense process called the unfolded protein response (UPR), which is important for alleviating stress and restoring normal function in a cell compartment, or organelle, known as the endoplasmic reticulum (ER).
The ER functions as a quality control checkpoint for proteins and also is a major site for metabolism. Normal ER function is important for maintaining glucose and lipid levels in the liver and other organs. Studies from both mouse models of obesity and humans have demonstrated that obesity impairs ER function.
The new study shows that obesity-related inflammation increases the production of nitric oxide in liver cells and that the nitric oxide modifies a key UPR regulator, IRE1. This modification impairs the UPR and prevents it from alleviating obesity-induced ER stress. Prolonged ER stress eventually leads to insulin resistance and Type 2 diabetes.
By introducing a version of the IRE1 protein that cannot be modified by nitric oxide, the researchers were able to ameliorate ER function in obese mice and improve metabolic control in the animals.
“Eventually, therapies that restore ER capacity and the adaptive capabilities of the UPR by interfering with NO-mediated protein nitrosylation or protecting key target molecules, may prove beneficial for both obesity and diabetes,” says Yang, who also is a member of the Fraternal Order of Eagles Diabetes Research Center at the UI and the Pappajohn Biomedical Institute.
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