title: Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B.
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 Ptp1b(fl/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.
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Owen
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: E K
authors.initials: EK
authors.lastname: Lees
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Mody
authors.affiliation: Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. Electronic address: m.delibegovic@abdn.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Delibegović
mesh_terms: D000818:Animals; D001835:Body Weight; D005215:Fasting; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019382:Human Growth Hormone; D053614:Janus Kinase 2; D058570:TOR Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Growth hormone; JAK2; Liver; PTP1B; STAT