Yale Researchers Find New Molecular Target for Obesity

New Haven, Conn. — Mice bred without the enzyme MKP-1 are resistant to weight gain despite consuming high fat foods and eating more than control mice, according to a research study published online in Cell Metabolism.

“The results from this study give us new molecular clues into how metabolic homeostasis is regulated and the possibility of new therapeutic avenues to specifically combat obesity,” said the senior author, Anton Bennett, associate professor, Department of Pharmacology. “Further research will be directed toward understanding how MKP-1 is involved in controlling the expression of genes that regulate body mass.”

Not only did the mice lacking the enzyme gain weight much more slowly, they had no trouble controlling blood glucose levels, although leanness often correlates with increased insulin sensitivity. “This was a surprising result and suggested that body mass regulation could be uncoupled from the direct actions of insulin signaling,” Bennett said.

Bennett’s laboratory is studying how protein tyrosine phosphatases are regulated and how these enzymes are involved in the control of cell signaling in health and disease. MKP-1 is among the family of enzymes that “switches off” protein functions.

While experiments on cultured cells have established that MKP-1 inactivates the MAP kinases, Bennett’s laboratory bred the mice to observe the action of MKP-1 in the intact organism.

Initially the mice appeared normal. However, the researchers noticed that the “knock out” mice gained weight much more slowly when fed a regular diet. Even when placed on a high fat diet, the knock out mice were still significantly more resistant to weight gain than the control mice.

The researchers discovered that MKP-1 knock out mice were able to maintain their leanness when fed high fat food because these mice burned calories at a significantly higher rate than control mice.

Bennett said the precise mechanism for how MKP-1 regulates energy expenditure is under investigation, but the results suggest that MKP-1 negatively regulates the activity of the MAP kinases in the major organs that are involved in energy metabolism.

Cell Metabolism 4: 61-73 (July 2006)

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