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New, Promising Target For The Battle Against Obesity

Obesity is a widespread disease that is described as an epidemic in many societies.

In addition to helping people shed unwanted pounds, an effective treatment for this disorder would likely have a huge impact on the prevention of obesity-related illnesses such as diabetes, stroke, heart disease and even cancer.

New research suggests that such a treatment may be closer than ever.

The hormone leptin plays an integral role in regulating body mass. When leptin binds to its protein receptor on cells in the brain region called the hypothalamus, feeding is suppressed and there is an increase in energy expenditure.

While it is well established that a mutation in leptin or the leptin receptor causes obesity, leptin itself has not proved useful as a treatment for obesity. In fact, most cases of obesity are associated with an increase in blood levels of leptin, suggesting that there is resistance to the protein in obese individuals.

Now, two studies published in the April issue of Developmental Cell identify a novel protein that regulates leptin signaling, and that may be a promising target for treatment of leptin resistance in obesity.

Dr. Michel Tremblay and colleagues from McGill University in Quebec and Dr. Barbara Kahn and colleagues from Harvard University both examined a signaling protein called protein tyrosine phosphatase 1B (PTP1B) and its effect on leptin signaling.

Because mice deficient in PTP1B are resistant to high fat diet-induced obesity, they hypothesized that PTP1B might regulate leptin signaling. Testing this idea, Dr. Tremblay's group found that mice lacking both leptin and PTP1B showed decreased weight gain and fat tissue, and had an increased metabolic rate, compared to mice lacking only leptin. In addition, the PTP1B-deficient mice showed an enhanced response to leptin-mediated weight loss.

Dr. Kahn's group found that PTP1B is present in the leptin-responsive cells of the hypothalamus and that PTP1B deficiency reduced the weight gain seen in mice whose leptin signaling was disrupted. Both groups found that PTP1B acts on the signaling protein Jak2 in the leptin signaling pathway.

Taken together, the results from these studies make the exciting prediction that pharmacological inhibitors of PTP1B may be useful as an alternative or supplement to leptin treatment of obesity.

[Contact: Dr. Michel L. Tremblay, Dr. Barbara B. Kahn]






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