To test this hypothesis the Salk team asked whether ER stress can induce gluconeogenesis in lean mice. Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB and together they switch on the genes necessary to increase glucose output. In insulin-resistant mice, however, the CRTC2 switch seems to get stuck in the "on" position and the cells start churning out glucose like sugar factories in overdrive.
Surprisingly, when postdoctoral researcher and first author Yiguo Wang, Ph.D., mimicked the conditions of ER stress in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, Wang found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a.
What's more, like jealous lovers CREB and ATF6a competing for CRTC2's affectionthe more ATF6a is bound to CRTC2, the less there is for CREB to bind to. "This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy," says Wang.
This observation led the researcher to ask what happens to ATF6a following the kind of persistent stress presented by obesity? They found that the levels of ATF6a go down when ER stress is chronically activated, compromising the cells' survival pathway and favoring the glucose production pathway; hyperglycemia wins in conditions
|Contact: Gina Kirchweger|