Shp2 protein plays a critical role in obesity

A team of researchers led by The Burnham Institute's Gen-Sheng Feng, Ph.D. has discovered that a protein called Shp2 plays a critical role in obesity. Published in Proceedings of the National Academy of Sciences, these results show that Shp2 has potential of becoming a novel pharmaceutical target for treatment of individuals suffering obesity and leptin resistance.

In 2003, the World Health Organization identified obesity as a growing global threat affecting more than 300 million people worldwide. Although it is commonly believed that obese individuals can overcome their condition by simply eating less and exercising more, compelling scientific data suggest that the heritability of obesity is greater than breast cancer, heart disease, or schizophrenia. Morbid obesity is considered as the disease of the twenty-first century, with the affected individuals at higher risk for diabetes, heart disease, hypertension and cancer, collectively known as metabolic syndrome.

Shp2, a Src homology 2-containing tyrosine phosphatase, was discovered by Dr. Feng and others over a decade ago. It is present in each cell type in the body and is implicated in a variety of growth factor or cytokine pathways present in these cells.

The physiological function of Shp2 is largely unknown. Whether it is active in multiple pathways or focused on a single pathway remains to be seen. In recent years, in vitro experiments suggest that Shp2 plays a role in regulating the protein leptin. Leptin, produced in fat cells, is a hormone that regulates body weight, metabolism, and reproduction. The primary action site for leptin is within the hypothalamus, located in the forebrain.

Dr. Feng and his colleagues took the investigation to the next level by looking at the role of Shp-2 in live mice. They used a highly advanced genetic engineering technique called "cell-type specific gene knockout" to breed a special kind of mouse in which Shp-2 was eliminated from the mouse's forebrain. The progeny were mice with early-onset obesity that had increased levels of leptin, insulin, glucose, and triglycerides. Furthermore, the mice could gain weight by eating normal amounts of food, which supports a role for Shp-2 in metabolism.

"Shp-2 has different functions in each cell," says Dr. Feng. "We found that in adult neuoronal cells, it's important function is to control metabolism. This hypothesis will be tested further, but it appears to present a target for the design of new anti-obesity drugs that could help individuals suffering from obesity by increasing their sensitivity to leptin."

Dr. Feng is an Associate Professor in the Burnham Institute's Program on Signal Transduction.

This work was supported by grants from the National Institutes of Health. Dr. Feng acknowledges with appreciation the American Diabetes Foundation, which supported the research that led to his discovery of the Shp2 tyrosine phosphatase early in his career.

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