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In mammals, blood sugar levels must be carefully balanced: too low, and the brain and other organs are starved; too high, and nerves, blood vessels and organs may be damaged. Thus, when mammals fast, even for brief periods such as during sleep, the pancreas releases glucagon, a hormone that stimulates the liver to produce glucose. Conversely, when mammals eat, an increase in pancreatic insulin instructs the liver to halt this activity. In obesity, this regulation tends to be lost, leading to insulin resistance — in which the liver becomes deaf to insulin's signals — and elevated blood sugar levels, or hyperglycaemia. Marc Montminy and his colleagues at the Salk Institute for Biological Studies in La Jolla, California, have now discovered a mechanism by which the protein CRTC2 (also known as TORC2) contributes to this problem (see page 534). Montminy tells Nature more.

What does CRTC2 do?

The CRTC2 protein functions as a genetic switch that triggers glucose production by the liver during fasting. We discovered that, in addition to responding to glucagon, CRTC2 can sense increases in stress in the endoplasmic reticulum (ER) — the cellular site that processes and folds newly synthesized proteins. Normally, ER stress acts as a brake on liver cells' production of glucose. But in obesity, the ER-stress pathway is chronically activated, so CRTC2's ability to cut glucose production is compromised. A component of the ER-stress brake, the protein ATF6, is also reduced, allowing the CRTC2 switch to boost glucose production, leading to hyperglycaemia and insulin resistance.

Can you fix this defect?

We were able to partly restore normal glucose regulation in obese mice by increasing the liver's production of ATF6. We inserted the ATF6 gene into an engineered adenovirus and injected this into obese mice. The virus then travelled to the liver, where it boosted the production of ATF6, restoring it to roughly normal levels. As a result, blood glucose levels stabilized.

How did you get the mice to become obese?

We fed them a Western-style diet in which 60% of the calories were provided by fat. After eight to ten weeks, the mice became obese and displayed physiological changes consistent with insulin resistance.

Does this work have implications for humans?

Developing drugs that modulate the ER-stress pathway in the liver could be of therapeutic benefit to obese individuals who are insulin resistant.