Shp2 as a therapeutic target for leptin resistance and obesity

Abstract

Most obese subjects exhibit leptin resistance, thus restricting the value of direct leptin administration for treatment of obesity. Understanding the leptin signalling mechanism has become crucial for design of novel therapeutic strategies for leptin-resistant/obese patients. The SH2-containing cytoplasmic tyrosine phosphatase Shp2 has recently been shown to play a critical role in leptin signalling and functions in hypothalamic control of energy balance and metabolism. Shp2 appears to downregulate the LepRb-STAT3 pathway while promoting extracellular-regulated kinase activation by leptin. Overall, Shp2 is a leptin signal enhancer, as evidenced by the obese and hyperleptinemic phenotype of mutant mice with Shp2 deleted in postmitotic forebrain neurons. Pharmaceutical enhancement of Shp2 activity may be a new approach worthy of consideration in clinical treatment of leptin resistance and obesity. This article discusses the significance of recent experimental data on Shp2 and also the prospects for using Shp2 as a therapeutic target for obese patients.

Keywords::

• diabetes
• leptin
• obesity
• Shp2
• tyrosine phosphatase

Acknowledgements

The work in the author’s laboratory has been supported by NIH grants GM53660 and CA78606. G.S.F. was a recipient of a career development award from American Diabetes Association (ADA). The author thanks Dr Cai Li and Dr Jian Li for critical reading of the manuscript and Ms Yvonne Montoya for assistance.