Potential Target for Treating Diabetes and Obesity Emerges from Mice Study

Researchers studying mice have identified a potential target for treating diabetes and obesity.

Scientists at Washington University School of Medicine in St. Louis, found that when the target protein was disabled, the animals became more sensitive to insulin and were less likely to get fat even when they ate a high-fat diet that caused their littermates to become obese.

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The researchers studied how the body manufactures fat from dietary sources such as carbohydrates. That process requires an enzyme called fatty acid synthase (FAS). Mice engineered so that they don't make FAS in their fat cells can eat a high-fat diet without becoming obese.

"Mice without FAS were significantly more resistant to obesity than their wild-type littermates," first author Irfan J. Lodhi, PhD, said.

"And it wasn't because they ate less. The mice ate just as much fatty food, but they metabolized more of the fat and released it as heat," he said.

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To understand why that happened, Lodhi, a research instructor in medicine, analyzed their fat cells.

Mice have two types of fat: white fat and brown fat. White fat stores excess calories and contributes to obesity. Brown fat helps burn calories and protects against obesity.

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In mice genetically blocked from making fatty acid synthase in fat cells, Lodhi and his colleagues noticed that the animals' white fat was transformed into tissue that resembled brown fat.

"These cells are 'brite' cells, brown fat found where white fat cells should be," Lodhi said.

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"They had the genetic signature of brown fat cells and acted like brown fat cells. Because the mice were resistant to obesity, it appears that fatty acid synthase may control a switch between white fat and brown fat. When we removed FAS from the equation, white fat transformed into brite cells that burned more energy."

Determining whether humans also have brown fat has been somewhat controversial throughout the years, but recent studies elsewhere have confirmed that people have it.

"It definitely exists, and perhaps the next strategy we'll use for treating people with diabetes and obesity will be to try to reverse their problems by activating these brown fat cells," senior investigator Clay F. Semenkovich, MD, said.

Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, said that the new work is exciting because FAS provides a target that may be able to activate brown fat cells to treat obesity and diabetes. But even better, he says it may be possible to target a protein downstream from FAS to lower the risk for potential side effects from the therapy.

Lodhi and Semenkovich noticed that in mice without FAS in their fat cells, activity of PPAR-alpha (the fat burner) was increased, while PPAR-gamma (the fat builder) activity decreased.

"There was decreased fat when we blocked PexRAP," Lodhi said.

"Those mice also had improved glucose metabolism, so we think that inhibiting either fatty acid synthase or PexRAP might be good strategies for treating obesity and diabetes," he added.

The findings are published online in the journal Cell Metabolism.

Source-ANI