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Eat less, weigh more? Enzyme makes lean mice 'susceptible' to dietary fat

Working with genetically engineered mice, Johns Hopkins scientists have interfered with the brain's ability to control an animal's response to a high-fat diet. The report, to be published in the latest issue of the Proceedings of the National Academy of Sciences online the week of May 1, is based on the identification of a gene - CPT1c - the brain needs to manage body weight.

According to the researchers, the CPT1c gene protects against weight gain caused by a high-fat diet. So-called knockout mice lacking the CPT1c gene gain more weight than their littermates carrying normal copies of the gene.

"We think our study reveals a direct weight management pathway," says Michael Wolfgang, Ph.D., a postdoctoral fellow in the Department of Biological Chemistry at The Johns Hopkins University School of Medicine and an author of the report. "CPT1c seems to allow the body to respond immediately to the level of nutrients and fat in the bloodstream."

Hopeful that the discovery has broad implications for understanding the genetic underpinnings of obesity and weight management, the Hopkins investigators say the work affirms the central role of the brain in managing hunger and satiety and offers up new targets for drugs that manipulate CPT1c. But none have been developed so far, says Wolfgang.

The newly discovered gene makes a protein found only in the brain, notably in the region that controls hunger, thirst and metabolism - the hypothalamus. Proteins similar to CPT1c are known to help break down fat to release energy to feed cells. Mice lacking the CPT1c gene are the same length as their littermates who carry normal copies of the gene but on average weigh 15 percent less when fed a low-fat diet.

Further analysis revealed that when deprived of food for four hours prior to feeding with standard laboratory mouse chow, the knockout mutant mice ate about 25 percent less food than their normal siblings. Therefore, the researchers conclude
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Contact: Audrey Huang
audrey@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
2-May-2006


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