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.
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.



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).



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.



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.
Protein Phosphorylation Research Group, Department of Experimental Medical Science, Lund University, BMC C11, Klinikgatan 28, 22242, Lund, Sweden.
Johanna
0000-0001-7337-4140
J
Säll
Lipid Laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Annie M L
AM
Pettersson
Lipid Laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Christel
C
Björk
Protein Phosphorylation Research Group, Department of Experimental Medical Science, Lund University, BMC C11, Klinikgatan 28, 22242, Lund, Sweden.
Emma
E
Henriksson
Glucose Transport and Protein Trafficking, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Sebastian
S
Wasserstrom
Protein Phosphorylation Research Group, Department of Experimental Medical Science, Lund University, BMC C11, Klinikgatan 28, 22242, Lund, Sweden.
Wilhelm
W
Linder
Diabetes and Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Yuedan
Y
Zhou
Diabetes and Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Ola
O
Hansson
Lipid Laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Daniel P
DP
Andersson
Surgery, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Mikael
M
Ekelund
Insulin Signal Transduction, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Eva
E
Degerman
Glucose Transport and Protein Trafficking, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Karin G
KG
Stenkula
Lipid Laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Jurga
J
Laurencikiene
Protein Phosphorylation Research Group, Department of Experimental Medical Science, Lund University, BMC C11, Klinikgatan 28, 22242, Lund, Sweden. olga.goransson@med.lu.se.
Olga
O
Göransson
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; C509079:SIK3 protein, human; D005947:Glucose
Gene and protein expression; Glucose uptake; HOMA-IR; Inflammation; Obesity; SIK2; SIK3; Salt-inducible kinase; Weight loss