Diabetes' Link To Obesity Broken In Mice

By genetically altering production of a factor found in skeletal muscle, scientists produced mice that can't get fat but do develop early signs of diabetes. Reversing the alteration produced mice that can become obese but do not develop diabetes.

The findings provide important insights for scientists struggling to find new ways to cope with the unprecedented epidemic of obesity now spreading through the United States and other nations. Obesity brings with it a range of health consequences including sharply increased risk of type 2 diabetes, the most common form of diabetes.

Scientists broke the link to improve their understanding of the network of factors that lead from obesity to the onset of diabetes. Based on what they learned, they applied a drug treatment in their new transgenic mice and in a different, previously established mouse line that suffers from obesity and a diabetes-like condition. In both groups, the drug increased insulin sensitivity, which is a primary goal of diabetes treatment.

"These results confirm that the links between obesity and diabetes show great promise as targets for new therapies that act as 'metabolic modulators' in muscle," says senior author Daniel P. Kelly, M.D., professor of medicine, of pediatrics and of molecular biology and pharmacology.

The study appears in the February 2005 issue of Cell Metabolism. It reveals new details of the activities of the peroxisome proliferator-activated receptors (PPARs), a family of receptors that affects the way cells respond to energy resources.

Diabetes disrupts the body's ability to manage energy resources including both fat and sugar. Insulin is a primary regulator of these resources. When the intake of calories exceeds the ability of the body to store them, insulin does not work as well, leading to an increase in blood sugar levels. The work by Kelly's group shows that this problem starts by diversion of fats to muscle, triggering an abnormal activation of PPAR. PPAR in turn sends signals to the cells to stop responding to insulin, resulting in hazardously high blood sugar levels.

Kelly's research group had previously shown that a member of the PPAR family, PPAR-alpha, was unusually active in heart and skeletal muscle of diabetic mice. PPAR-alpha normally becomes active in response to fats. It "revs up" the machinery cells use to make energy from fat, according to Kelly.

"It's an adaptive response that helps the cell deal with all the fat that's coming in, but our notion was that it might also play a role in the development of diabetes," he explains. "We thought PPAR-alpha might also be telling cells, look, we have all this fat coming in, so we're not going to need glucose to make energy, so let's shut down glucose burning. And that's exactly what happens in diabetes."

To test their ideas, Kelly and lead author Brian N. Finck, Ph.D., research instructor in medicine, engineered a line of mice with extra PPAR-alpha in their skeletal muscle. They found the mice's skeletal muscle cells could "chew up" fat at remarkable speeds, preventing obesity even when the mice were fed a high-fat diet.

Although they were lean, the mice were also "on their way to becoming diabetic," according to Kelly. Insulin resistance and glucose intolerance -- two key harbingers of diabetes -- increased in the mice. Kelly's group traced the glucose intolerance to PPAR-alpha's ability to shut down genes involved in glucose uptake and use.

When Kelly's lab tested a line of mice where PPAR-alpha had been genetically knocked out, they found the reverse was true. The mice could get just as obese as normal mice on a high-fat diet, but they did not develop early signs of diabetes.

Based on what they learned about PPAR-alpha's effects, scientists gave a drug that inhibited an important enzyme in the processes that let muscle cells make energy from fat. PPAR-alpha normally activates this enzyme as part of its efforts to accelerate fat metabolism, and blocking it essentially tricked the cell into thinking that PPAR-alpha was no longer activated. Insulin sensitivity increased as a result.

To follow up, Kelly's lab is attempting to rescue the new mouse line from glucose intolerance and insulin resistance. PPAR-alpha seems to convince cells that they don't need glucose because they have plenty of energy available from fat, so Kelly will try to increase energy demand or trick cells into thinking they have less energy available.

"One obvious experiment is to exercise the animals, increasing their muscle energy requirements to see if we can make them more insulin sensitive," Kelly says. "Another option is to develop ways to decrease the cellular accumulation of a compound known as ATP, which is the key product of cellular energy-making processes."

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Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP. "A potential link between muscle peroxisome proliferator-activated receptor alpha signaling and obesity-related diabetes." Cell Metabolism, February 2005.

Funding from the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.

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