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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

Säll, Johanna LU ; Pettersson, Annie M L; Björk, Christel LU ; Henriksson, Emma LU ; Wasserstrom, Sebastian LU ; Linder, Wilhelm; Zhou, Yuedan LU ; Hansson, Ola LU ; Andersson, Daniel P LU and Ekelund, Mikael LU , et al. (2017) In Diabetologia 60(2). p.314-323
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Diabetologia
volume
60
issue
2
pages
314 - 323
publisher
Springer Verlag
external identifiers
  • scopus:84994353608
  • wos:000391359800013
ISSN
1432-0428
DOI
10.1007/s00125-016-4141-y
language
English
LU publication?
yes
id
3ce5cbc8-25aa-4c23-819e-963c9a3ac6a3
date added to LUP
2016-11-14 17:08:06
date last changed
2018-01-07 11:35:09
@article{3ce5cbc8-25aa-4c23-819e-963c9a3ac6a3,
  abstract     = {<p>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.</p><p>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).</p><p>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.</p><p>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.</p>},
  author       = {Säll, Johanna and Pettersson, Annie M L and Björk, Christel and Henriksson, Emma and Wasserstrom, Sebastian and Linder, Wilhelm and Zhou, Yuedan and Hansson, Ola and Andersson, Daniel P and Ekelund, Mikael and Degerman, Eva and Stenkula, Karin G and Laurencikiene, Jurga and Göransson, Olga},
  issn         = {1432-0428},
  language     = {eng},
  number       = {2},
  pages        = {314--323},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {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},
  url          = {http://dx.doi.org/10.1007/s00125-016-4141-y},
  volume       = {60},
  year         = {2017},
}