( Scientists at the Salk Institute for Bi...)Chewing up a key regulator of fat synthesis keeps mice lean despite a high-fat diet

Genetically engineered mice, in which the pathway was constantly revved up, were protected from the ravages of a high-fat diet, the Salk team led by Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology reports in this week's issue of Science.

"These mice were able to deal with a high-fat diet much better than their normal counterparts," Montminy says. "They stayed lean and were much more sensitive to insulin, although they ate more," he adds.

In humans, a high-fat diet ?one heavy on red and processed meats like hot dogs and sausages, refined grains, fried foods and sweets ?increases the risk of fatty liver disease, which may eventually lead to type 2 diabetes, especially in people who are overweight and out of shape.

The engineered mice consumed an equally high-fat diet but did not gain weight, indicating that fat storage pathways can be tweaked. "Maybe the most amazing finding is that these mice are protected from fatty liver disease, a serious problem in obese individuals with insulin resistance," says Montminy.

Our body's ability to store fat requires the activity of the enzyme acetyl-coenzyme A carboxylase, or ACC. When we fast, the body starts to burn fat while simultaneously shutting down ACC through a chemical modification called phosphorylation.

The Salk researchers found that a critical protein called TRB3 orchestrates a second chemical modification of ACC, known as ubiquitination, which gets rid of the enzyme altogether. "In this parallel pathway, TRB3 serves as a go-between for an enzyme that marks ACC for degradation," says Jose Heredia, a graduate student in Montminy's lab.

TRB3 levels in adipose tissue usually rise
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Source:Salk Institute