title: Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B.
abstract: 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.
authors.affiliation: McGill Cancer Center, McGill University, H3G 1Y6, Montreal, Quebec, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.forename: Noriko
authors.initials: N
authors.lastname: Uetani
authors.forename: Paul D
authors.initials: PD
authors.lastname: Simoncic
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Chaubey
authors.forename: Ailsa
authors.initials: A
authors.lastname: Lee-Loy
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D005838:Genotype; D007031:Hypothalamus / Q000502:physiology; D053614:Janus Kinase 2; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D015430:Weight Gain
chemical_list: D004268:DNA-Binding Proteins; D020738:Leptin; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse