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PTP1B regulates leptin signal transduction in vivo

Janice M Zabolotny1, Kendra K Bence-Hanulec, Alain Stricker-Krongrad

  • 1Division of Endocrinology and Metabolism, Division of Hematology and Oncology, Department of Medicine, Boston, MA, USA.

Developmental Cell
|April 24, 2002
PubMed

Insights

Mice lacking protein-tyrosine phosphatase 1B (PTP1B) resist obesity by showing enhanced sensitivity to leptin signaling. This phosphatase likely targets Jak2, suggesting PTP1B as a potential therapeutic target for obesity.

Area of Science:

  • Metabolism and Endocrinology
  • Molecular Biology
  • Obesity Research

Background:

  • Mice deficient in protein-tyrosine phosphatase 1B (PTP1B) exhibit insulin hypersensitivity and obesity resistance.
  • The precise molecular mechanisms underlying PTP1B-mediated obesity resistance remained largely undetermined.

Purpose of the Study:

  • To elucidate the role of PTP1B in regulating leptin signaling pathways.
  • To investigate PTP1B's potential as a therapeutic target for leptin resistance in obesity.

Main Methods:

  • Investigated PTP1B's interaction with leptin receptor-associated kinase, Jak2, using transfection studies.
  • Examined PTP1B expression in hypothalamic regions crucial for leptin response.
  • Assessed leptin sensitivity, body fat ratios, and Stat3 phosphorylation in PTP1B-deficient mice.
  • Utilized gold thioglucose treatment to ablate hypothalamic neurons and observe its effect on obesity resistance.

Main Results:

  • PTP1B dephosphorylates Jak2, a key mediator of leptin signaling.
  • PTP1B-deficient mice displayed reduced leptin/body fat ratios and heightened leptin sensitivity.
  • Enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation was observed in PTP1B knockout mice.
  • Ablation of leptin-responsive neurons partially reversed obesity resistance in PTP1B-deficient mice.

Conclusions:

  • PTP1B plays a critical role in regulating leptin signaling in vivo, likely through its action on Jak2.
  • These findings identify PTP1B as a potential therapeutic target for combating leptin resistance and obesity.

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