PTP1B regulates leptin signal transduction in vivo.
Mice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons. Compared to wild-type littermates, PTP1B(-/-) mice have decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation. Gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially overcomes resistance to obesity in PTP1B(-/-) mice. Our data indicate that PTP1B regulates leptin signaling in vivo, likely by targeting Jak2. PTP1B may be a novel target to treat leptin resistance in obesity.
Zabolotny
Janice M
JM
Division of Endocrinology and Metabolism, Division of Hematology and Oncology, Department of Medicine, Boston, MA, USA.
Bence-Hanulec
Kendra K
KK
Stricker-Krongrad
Alain
A
Haj
Fawaz
F
Wang
Yongping
Y
Minokoshi
Yasuhiko
Y
Kim
Young-Bum
YB
Elmquist
Joel K
JK
Tartaglia
Louis A
LA
Kahn
Barbara B
BB
Neel
Benjamin G
BG
D000818:Animals; D019556:COS Cells; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology; D053614:Janus Kinase 2; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009765:Obesity / 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; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D015430:Weight Gain
D020738:Leptin; D011518:Proto-Oncogene Proteins; 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