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Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals : implications for insulin signalling and glucose uptake in human adipocytes

Author:
  • Johanna Säll
  • Annie M L Pettersson
  • Christel Björk
  • Emma Henriksson
  • Sebastian Wasserstrom
  • Wilhelm Linder
  • Yuedan Zhou
  • Ola Hansson
  • Daniel P Andersson
  • Mikael Ekelund
  • Eva Degerman
  • Karin G Stenkula
  • Jurga Laurencikiene
  • Olga Göransson
Publishing year: 2017-02
Language: English
Pages: 314-323
Publication/Series: Diabetologia
Volume: 60
Issue: 2
Document type: Journal article
Publisher: Springer Verlag

Abstract english

AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes.

METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01).

RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes.

CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Protein Phosphorylation
  • Glucose Transport and Protein Trafficking
  • Diabetes and Endocrinology
  • Insulin Signal Transduction
  • ISSN: 1432-0428
Eva Degerman
E-mail: eva [dot] degerman [at] med [dot] lu [dot] se

Professor

Insulin Signal Transduction

+46 46 222 85 83

+46 70 885 83 62

BMC C1121b

66

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00