Fat's fate depends on its source

A healthy metabolism requires a healthy dose of fat, suggests a new study published in the May issue of Cell Metabolism. Fats taken in directly from the diet or generated from sugars spark a cascade of gene activity in the liver necessary for healthy blood levels of sugar, cholesterol, and other fats, according to the researchers.

Old fat stores alone failed to set those critical metabolic pathways in motion, they found. The findings in mice suggest that normal metabolism requires so-called "new" fat--further evidence that a healthy diet should include an adequate source of fat.

"De novo synthesis of fat is an energy-expensive process whose role in adult mammals is poorly understood," said study senior author Clay Semenkovich, of Washington University School of Medicine. "The current study supports the notion that the source of fats affects their physiology. New fats are required to burn fat normally and to maintain glucose and cholesterol levels within the normal range.

"These findings underscore the importance of a balanced diet for healthy metabolism and weight loss," he added.

The results further suggest that specially engineered fats might boost healthy liver metabolism, offering an alternative mechanism for fighting chronic diseases, including obesity, diabetes, and heart disease, Semenkovich said.

The researchers inactivated fatty-acid synthase, an enzyme that generates new fat from carbohydrates, in the livers of mice. When fed a diet completely lacking fat, the mice developed low blood sugar and fatty liver. Both conditions were reversed when the researchers restored fat to the animals' diets.

"It is quite paradoxical," Semenkovich said. "When we inactivated fatty-acid synthase in the liver and eliminated fat in the diet, the animals became sick, with livers full of fat."

Further study found that, in the absence of new fat, the mice exhibited a marked decline in the activity of genes critical for the metabolism of glucose, fatty acids, and cholesterol. Those genes are normally targeted by PPARa, a key energy management gene activated by fatty acids.

"In short, all fatty acids are not created equal, at least in the liver," Semenkovich said.

The findings suggest that products of fatty acid synthesis regulate glucose, lipid, and cholesterol metabolism by activating distinct pools of PPARa in the liver. Further study is required to elucidate the mechanism by which nutrient sensors in the body distinguish between different sources of fat, the researchers said.

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The researchers include Manu V. Chakravarthy, Zhijun Pan, Yimin Zhu, Karen Tordjman, Jochen G. Schneider, Trey Coleman, John Turk, and Clay F. Semenkovich of Washington University School of Medicine in St. Louis. This work was supported by NIH grants, Clinical Nutrition Research Unit, Diabetes Research and Training Center, and Mass Spectrometry Resource.

Chakravarthy, M.V., Pan, Z., Zhu, Y., Tordjman, K., Schneider, J.G., Coleman, T., Turk, J., and Semenkovich, C.F. (2005). "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 1, 309-322. www.cellmetabolism.org

Source : Cell Press