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Sunday, March 22, 2009 | Scientists at Salk Institute for Biological Studies are using fat mice and skinny worms to figure out how, on a molecular level, our bodies cope with high-fat diets, and how genetics and diet restriction might affect our longevity.

If researchers can identify the gene families involved — and they say they are getting closer — it could mean entirely new drug therapies and other treatment approaches for the maladies associated with overeating and old age.

The mice are key to a discovery made by the lab of Salk biologist and medical doctor Marc Montminy regarding the role obesity plays in type II diabetes. Montminy’s lab found a molecular switch in the fat tissue of obese mice that helps determine whether the mouse will become insulin resistant, or diabetic. The discovery, published in the March issue of Cell Metabolism, could lead to drug therapies that would help protect obese people from the disease.

Next door, molecular biologist Andrew Dillin is using millimeter-long round worms to show that calorie counting does matter. In 2007, Dillin and his colleagues found a gene in the worms that plays a role in the worm living a longer and healthier life provided it is fed a severely calorie-restricted diet. And in the coming months Dillin said he will publish a paper that focuses on other genes involved.

We’ve long been aware that our diets affect our health and longevity. As Morgan Spurlock showed in his documentary “Super Size Me,” the detrimental effects of a high-fat diet (in his case nothing but McDonald’s) can show up in less than a month. One of the most common, and deadly, of these effects is diabetes. More than 23 million people in the United States suffer from diabetes, and another 57 million have pre-diabetic symptoms, according to recent statistics cited by the Salk Institute.

On the other end of the spectrum, a cottage industry has grown up around the benefits of routine fasting and other forms of calorie restriction. Bizarre diet regimens involving combinations like cayenne pepper and lemon juice have been touted as youth potions.

But researchers have had a hard time showing just how being fat makes people diabetic. And there is, as of yet, no definitive proof that calorie restriction leads to longer lives in humans. Those are the conundrums that keep Montminy and Dillin coming to work everyday.

The key hormone for diabetics is insulin, which is produced by the pancreas and influences a switch in the liver that goes on or off depending on when we are eating and when we are fasting. When we are fasting, the switch goes on and the liver produces blood sugar, or glucose, which is needed to keep oxygen flowing to our organs, the most important being the brain.

When we are eating, the switch goes off and the liver stops producing blood sugar because we are getting enough from our food. When a person becomes diabetic, that switch malfunctions and the body doesn’t know the difference from its feeding and fasting states. As a result, blood sugar levels skyrocket. Fat helps create this malfunction in many diabetic and pre-diabetic people.

“Why the fat does this is the big question,” said Montminy, who is both a medical doctor and a Ph.D. “That is the central focus of our lab — what’s the defect?”

Enter the obese mice. Montminy and his colleagues identified the switch in the livers of mice — a protein called CREB — that orchestrates the response to fasting. When blood sugar levels ran low, the CREB increased glucose production in the liver.

But they also found that CREB was activated in the fat tissue of insulin resistant, obese mice. So the scientists created a synthetic protein that blocked the activation of CREB in the fat tissue of mice. And when they fed the mice a high fat, junk-food-like diet, the mice became obese, but not insulin resistant.

If this works in humans it means that a higher risk for diabetes might someday fall down on the list of the downsides of being obese. “We think it is a major pathway that may be amenable to drug development,” Montminy said.

In Dillin’s lab the focus is on how much, or more precisely, how little an organism eats. He wants to know why round worms that are put on a severely calorie-restricted diet live much longer than those fed normal diets. He says he’s getting close to the answer.

If he finds it, it could revolutionize how people grow old.

“Reducing diet plays a role in every age-related disease there is — diabetes, cancer, heart failure,” Dillin said. “If we can figure out the (genetic) pathway that controls diet restriction, we can control the onset of all these diseases.”

Since the 1930s, researchers have known long periods of severe calorie restriction can significantly increase the quality and length of life in worms, mice and fruit flies. And Dillin is convinced that in this way the genes of these lower forms of life are identical to human genes.

But the calorie restriction that has increased longevity in worms and other species has not been proven to work the same way in humans. And even if it would, the required diet wouldn’t be equivalent to refusing a second helping at dinner or going on Atkins. “It’s going to your recommended diet, which none of us are on, and then reducing that by another 30 to 40 percent,” Dillin said. “It is really, really hard to get on that diet.”

So Dillin’s goal is to create a drug that tricks the body into to thinking that it is on a calorie restricted diet, when it isn’t. But to do that he has to fully understand the genetics of how the body deals with the food it consumes.

His lab made a significant step toward that end in 2007, when they found that worms missing one gene did not live longer on calorie-restricted diets. This was an important step. However, genes do not function independently.

“Now we have to figure out what the entire pathway is,” Dillin said. “What other genes are coordinating with this one?”

Please contact David Washburn directly at david.washburn@voiceofsandiego.org with your thoughts, ideas, personal stories or tips. Or set the tone of the debate with a letter to the editor.

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