CRTC2 mouse study shows switch gets stuck in the on position.

Researchers at the Salk Institute for Biological Studies have figured out that obesity sets the stage for diabetes through a condition known as ER (endoplasmic reticulum) stress, which is created by a high fat diet and overly activated in obese people, triggering aberrant glucose production in the liver.

The study, which appears June 21 in the advanced online edition of Nature, illustrates how the transcriptional switch CRTC2—that normally teams up with the CREB protein to turn on the genes necessary to increase glucose output—gets fixed in the on position in insulin-resistant mice and begins to churn out too much glucose. 

“When a cell starts to sense stress a red light goes on, which slows down the production of proteins,” explains Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology at the Salk Institute. “This process, which is known as ER stress response, is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. We asked whether chronic ER stress in obesity leads to abnormal activation of the fasting switch that normally controls glucose production in the liver.”

When the team 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. Investigators discovered that in this scenario, CRTC2 did not bind to CREB but instead, joined forces with another factor called ATF6a. CREB and ATF6a compete for CRTC2. The more ATF6a is bound to CRTC2, the less there is for CREB to bind to. That mechanism ensures that a cell in survival mode automatically shuts down glucose production, saving energy.

The team also 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. Therefore, hyperglycemia wins in conditions of persistent stress.

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