Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

C. Owen, E.K. Lees, N. Mody, M. Delibegovic

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13 Citations (Scopus)

Abstract

Protein tyrosine phosphatase 1B (PTP1B) regulates various signalling pathways including insulin, leptin, IGF-1 and growth hormone (GH) signalling. Transmission of the GH signal depends on Janus kinase 2 (JAK2), which is how PTP1B is thought to modulate GH signalling in the liver, based on studies utilising global PTP1B knockout mice (Ptp1b−/−). Here, we investigated the liver-specific role of PTP1B in GH signalling, using liver-specific Ptp1b−/− mice (alb-crePtp1b−/−), under physiological (chow) or insulin resistant (high-fat diet [HFD]) feeding conditions. Body weight and adiposity were comparable between female alb-crePtp1b−/− and Ptp1bfl/fl control mice. On chow diet, under 48-hour fasting GH-resistant conditions, GH stimulation in vivo led to a robust stimulation of the JAK-STAT signalling pathway. Alb-crePtp1b−/− mice exhibited significantly higher GH-induced JAK2 phosphorylation and SOCS3 gene expression post-GH stimulation. However, STAT3, STAT5 and ERK1/2 phosphorylation and SOCS2 gene expression were similar between groups. Interestingly, GH-induced mTOR phosphorylation was significantly higher in alb-crePtp1b−/− mice 5-min post-GH stimulation compared to controls, revealing this part of the pathway under direct control of PTP1B. Under ad lib HFD-fed conditions, GH-induced STAT5 phosphorylation significantly increased in alb-crePtp1b−/− mice only, with no alterations in the controls. Overall, our data demonstrate that liver-specific PTP1B deletion leads to significant alterations in GH signalling with increased JAK2, STAT5 and mTOR phosphorylation and SOCS3 gene expression.
Original languageEnglish
Pages (from-to)95-101
Number of pages7
JournalDiabetes & Metabolism
Volume41
Issue number1
Early online date16 Jun 2014
DOIs
Publication statusPublished - Feb 2015

Bibliographical note

Acknowledgements

We would like to thank Benjamin Neel (Campbell Family Cancer Research Institute, Ontario Cancer Institute, University of Toronto), Barbara Kahn (Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Centre, Boston) and Dr. Kendra Bence (Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania) for Ptp1b floxed mice. Carl Owen and Emma Katherine Lees are recipients of BBSRC doctoral-training studentships. Mirela Delibegovic and Nimesh Mody are funded by British Heart Foundation (PG/11/8/28703 and FS/09/026), EFSD/Lilly European Diabetes Programme Grant (EFSD/Lilly 2011) and Tenovus Scotland (G13/07).

Keywords

  • liver
  • PTP1B
  • JAK2
  • STAT
  • growth hormone

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