When levels of free protein p85 were increased in the livers of severely obese, diabetic mice, researchers at Children’s Hospital Boston-Harvard Medical School and the University of Tokyo saw improved glucose tolerance and reduced blood glucose levels. The effect lies in the influence of p85 on the transcription factor XBP-1 (X-box binding protein 1), the scientists said. Under the influence of p85, XBP-1 normally moves to the nucleus and turns on genes for numerous chaperone proteins, which reduce stress on the endoplasmic reticulum (ER) by aiding and stabilizing the folding of proteins that are produced there and then dispatched to do their jobs in the cell. In previous work, the authors had shown that the brain, liver, and fat cells of obese mice have increased stress in the ER. In the presence of obesity, the ER is overwhelmed and its operations break down. This so-called "ER stress" activates a cascade of events that suppress the body's response to insulin, and is a key link between obesity and type 2 diabetes. Until now, however, researchers haven't known precisely why obesity causes ER stress to develop. Senior author Dr. Umut Ozcan and colleagues have now shown that XBP-1 is unable to function properly in obese mice. Instead of traveling to the cell nucleus and turning on chaperone genes, XBP-1 becomes stranded. Probing further, the researchers found the reason: XBP-1 fails to interact with p85, which is part of an important protein (phosphotidyl inositol 3 kinase or PI3K) that mediates insulin's effect of lowering blood glucose levels. Dr. Ozcan's group identified a new complex of p85 proteins in the cell, and showed that normally, when stimulated by insulin, p85 breaks off and binds to XBP-1, helping it get to the nucleus.
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