Protein may be new target for obesity, diabetes therapies

Molecule regulates flip of a metabolic switch

A little bit of stress might be just what the doctor ordered to combat obesity and diabetes.

A new study in mice finds that a protein that plays a role in responding to certain kinds of stress may help regulate a metabolic pathway important for controlling blood sugar, burning fat and even making tumors grow. The study shows that the protein, known to play a role in aging (SN: 1/31/09, p. 13), is part of a protein family that has its finger on the pulse of both major pathways cells use to make energy, says Leonard Guarente, a molecular biologist at MIT who was not involved in the research.

The study indicates that the protein, known as sirtuin 6, or SIRT6, is what’s known as a master regulator, in this case helping cells switch between oxidative metabolism, the major form of energy production in cells; and anaerobic glycolysis, a less efficient way of making energy and can be tapped when oxygen or nutrients are in short supply. The anaerobic form of glycolysis needs more glucose to generate the same amount of energy as oxidative processes. The study, which appears in the Jan. 22 Cell, could lead the way to new therapies for diabetes and obesity.

Sirtuins are a family of proteins found in many organisms from yeast to humans. The most famous of the seven sirtuin proteins in humans, SIRT1, has been studied as a possible antiaging compound. That protein also helps regulate oxidative metabolism. Until recently, not much was known about the roles of other sirtuins.

Mice that lack SIRT6 seem normal at birth but die a few weeks later of hypoglycemia, or low blood sugar. No one knew how absence of the sirtuin protein could affect blood sugar levels so dramatically, says Raul Mostoslavsky, a molecular biologist at Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. In the new study, Mostoslavsky and his colleagues show that SIRT6 works with a stress-response protein known as Hif1alpha to control when and whether cells switch to anaerobic glycolysis.

Hif1alpha was already known to go to work when oxygen or glucose levels drop. Under such stress, the protein turns on genes involved in glycolysis and inhibits oxidative metabolism. During the stress of heavy exercise, for example, this switch occurs in muscles and leads to the buildup of lactate, which is responsible for feeling the burn after a workout. The new work demonstrates that SIRT6 acts as a safeguard mechanism to prevent Hif1alpha from becoming active when it is not supposed to.

When SIRT6 is missing or not working correctly, Hif1alpha inappropriately turns on anaerobic glycolysis and, the researchers found, turns off mitochondria, the cellular power plants where oxidative metabolism takes place.

That explains why mice missing SIRT6 become hypoglycemic, Mostoslavsky says. The animals burn all of their glucose trying to make enough energy to stay alive. For the first 10 to 12 days of life, these mice manage, but eventually the animals burn through all of their reserves, including fat stores, and die.

“Since the mice are using glucose for glycolysis, they are burning fat like crazy,” Mostoslavsky says.

Mostoslavsky suggests that drugs could be designed to turn down SIRT6 activity slightly. Targeting the protein might help diabetics lower blood sugar by burning that extra sugar for energy. And obese people might be able to lose weight by turning excess fat into energy the way SIRT6 mutant mice do.

The researchers don’t present any data in the new study on SIRT6’s role in aging, but the team’s finding that the protein is involved in stress responses and metabolism supports previous work showing the protein’s important in the aging process, says Matthew Kaeberlein, a molecular biologist at the University of Washington in Seattle.

“Inhibition of SIRT6 may be beneficial, but that’s pretty speculative,” Kaeberlein says. On the other hand, he speculates, turning up SIRT6 activity could help starve tumors, which often use glycolysis to generate energy.

“It’s a very interesting sirtuin, for sure,” says Guarente. “This study really adds meat to the bones” in fleshing out an understanding of how sirtuins help regulate metabolism.

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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