Attenuation of Leptin Action and Regulation of Obesity by Protein Tyrosine Phosphatase 1B

• Published in: Developmental cell 2002-04, Vol.2 (4), p.497-503
• Main Authors: Cheng, Alan, Uetani, Noriko, Simoncic, Paul D., Chaubey, Vikas P., Lee-Loy, Ailsa, McGlade, C.Jane, Kennedy, Brian P., Tremblay, Michel L.
• Format: Article
• Language: English
• Subjects: Animals; DNA-Binding Proteins - metabolism; Genotype; Hypothalamus - physiology; Janus Kinase 2; Leptin - genetics; Leptin - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity - genetics; Obesity - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins; STAT3 Transcription Factor; Trans-Activators - metabolism; Weight Gain
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/S1534-5807(02)00149-1

Common obesity is primarily characterized by resistance to the actions of the hormone leptin. Mice deficient in protein tyrosine phosphatase 1B (PTP1B) are resistant to diabetes and diet-induced obesity, prompting us to further define the relationship between PTP1B and leptin in modulating obesity. Leptin-deficient ( Lep ob/ob ) mice lacking PTP1B exhibit an attenuated weight gain, a decrease in adipose tissue, and an increase in resting metabolic rate. Furthermore, PTP1B-deficient mice show an enhanced response toward leptin-mediated weight loss and suppression of feeding. Hypothalami from these mice also display markedly increased leptin-induced Stat3 phosphorylation. Finally, substrate-trapping experiments demonstrate that leptin-activated Jak2, but not Stat3 or the leptin receptor, is a substrate of PTP1B. These results suggest that PTP1B negatively regulates leptin signaling, and provide one mechanism by which it may regulate obesity.