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

Johanna Säll,Wilhelm Linder,Yuedan Zhou,Annie M L Pettersson,Mikael Ekelund,Emma Henriksson,Karin G Stenkula,Olga Göransson,Jurga Laurencikiene,Daniel P Andersson,Eva Degerman,Sebastian Wasserstrom,Ola Hansson,Christel Björk

doi:10.1007/s00125-016-4141-y

Johanna Säll, Wilhelm Linder + Show 12 more

Open Access

https://doi.org/10.1007/s00125-016-4141-y

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Journal: Diabetologia	Publication Date: Nov 2, 2016
Citations: 31	License type: open-access

Affiliation: Lund University, Karolinska Institutet

Abstract

Aims/hypothesisSalt-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.MethodsSIK 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).ResultsWe 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/interpretationThis 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.

Highlights

The salt-inducible kinases (SIKs)—SIK1, SIK2 and SIK3— are related to AMP-activated protein kinase (AMPK), a master regulator of cellular and whole body energy homeostasis [1]
We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change
In order to estimate the contribution of each isoform to total SIK activity, we performed in vitro kinase assays of SIK2 and SIK3 in human adipose tissue or adipocyte lysates

Summary

Introduction

The salt-inducible kinases (SIKs)—SIK1, SIK2 and SIK3— are related to AMP-activated protein kinase (AMPK), a master regulator of cellular and whole body energy homeostasis [1]. SIK2 is highly expressed in adipose tissue and increases during adipocyte differentiation [9,10,11], while SIK3 displays a more ubiquitous expression [12]. Together SIKs control diverse cellular processes including the regulation of glucose and lipid metabolism in rodent liver [13,14,15,16,17,18] and adipose tissue [10, 19, 20]. A previous study described increased expression and activity of SIK2 in white adipose tissue (WAT) from obese db/db mice [9], suggesting a role for SIK2 in obesity and diabetes. SIK3 has been linked to metabolism, and Sik3-/- mice display disturbed lipid and glucose homeostasis [14, 17]. Genetic variations in SIK3 have been associated with dyslipidaemia and obesity in humans [21]

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