The role of salt-inducible kinase in the control of hepatic gluconeogenesis
type: CreativeWork
description: Regulation of hepatic gluconeogenesis by hormones insulin and glucagon is central to glucose homeostasis. Recent work has proposed that amongst the salt inducible kinase isoforms (SIK1, 2 and 3), members of the AMPK-related kinase family, the SIK2 isoform may play a role as signalling mediator in the control of insulin- and glucagon-regulated hepatic gluconeogenesis. However, the mechanisms of the hormonal-regulation of SIK2 in liver remain controversial, with much of the data based on the studies in non-hepatic tissues/cells. Therefore, the exact molecular regulation of SIK2 by these hormones in the liver required robust and intensive molecular/biochemical research coupled to physiological readout (e.g. gluconeogenesis). My studies with phosphopeptide mapping by mass spectrometry followed by verification with well-characterised phospho-specific antibodies revealed that SIK2 was phosphorylated on Ser343, Ser358, Thr484 and Ser587 in response to glucagon and fasting but not following insulin treatment or refeeding in primary hepatocytes and liver in vivo, respectively. Unexpectedly, fasting- or glucagon-stimulated phosphorylation of SIK2 (individually or in combination) did not directly modulate kinase activity of SIK2 and its subcellular localisation. These findings collectively questioned the role of SIK2 in hepatic gluconeogenesis. Thus to establish the role of SIK2 in vivo, liver-specific SIK2 knock-out mice were generated and analysed (in collaboration with Dr Marc Foretz, Institut Cochin, Paris). Surprisingly, the liver-specific SIK2 knock-out mice displayed normal blood glucose levels and gluconeogenic gene expression in both fasted and refed states compared to the control mice. The primary hepatocytes from these liver-specific SIK2 knock-out mice had unaltered basal and Bt2-cAMP-stimulated glucose production and gluconeogenic gene expression compared to the control hepatocytes. These suggest that SIK2 is either not involved in hepatic gluconeogenesis or its l…
abstract: Regulation of hepatic gluconeogenesis by hormones insulin and glucagon is central to glucose homeostasis. Recent work has proposed that amongst the salt inducible kinase isoforms (SIK1, 2 and 3), members of the AMPK-related kinase family, the SIK2 isoform may play a role as signalling mediator in the control of insulin- and glucagon-regulated hepatic gluconeogenesis. However, the mechanisms of the hormonal-regulation of SIK2 in liver remain controversial, with much of the data based on the studies in non-hepatic tissues/cells. Therefore, the exact molecular regulation of SIK2 by these hormones in the liver required robust and intensive molecular/biochemical research coupled to physiological readout (e.g. gluconeogenesis). My studies with phosphopeptide mapping by mass spectrometry followed by verification with well-characterised phospho-specific antibodies revealed that SIK2 was phosphorylated on Ser343, Ser358, Thr484 and Ser587 in response to glucagon and fasting but not following insulin treatment or refeeding in primary hepatocytes and liver in vivo, respectively. Unexpectedly, fasting- or glucagon-stimulated phosphorylation of SIK2 (individually or in combination) did not directly modulate kinase activity of SIK2 and its subcellular localisation. These findings collectively questioned the role of SIK2 in hepatic gluconeogenesis. Thus to establish the role of SIK2 in vivo, liver-specific SIK2 knock-out mice were generated and analysed (in collaboration with Dr Marc Foretz, Institut Cochin, Paris). Surprisingly, the liver-specific SIK2 knock-out mice displayed normal blood glucose levels and gluconeogenic gene expression in both fasted and refed states compared to the control mice. The primary hepatocytes from these liver-specific SIK2 knock-out mice had unaltered basal and Bt2-cAMP-stimulated glucose production and gluconeogenic gene expression compared to the control hepatocytes. These suggest that SIK2 is either not involved in hepatic gluconeogenesis or its l…
author: Patel, Kashyap
language: eng
date published: 2014
date modified: 2026-07-24T02:07:52Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee