Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B

Dev Cell. 2002 Apr;2(4):497-503. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • DNA-Binding Proteins
  • Leptin
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse