Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 2/2017

Open Access 01-02-2017 | Article

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

Authors: 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

Published in: Diabetologia | Issue 2/2017

Login to get access

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 (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.
Appendix
Available only for authorised users
Literature
1.
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262CrossRefPubMed
2.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934CrossRefPubMed
3.
Lizcano JM, Goransson O, Toth R et al (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23:833–843CrossRefPubMedPubMedCentral
4.
Wang Z, Takemori H, Halder SK, Nonaka Y, Okamoto M (1999) Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal. FEBS Lett 453:135–139CrossRefPubMed
5.
Bertorello AM, Pires N, Igreja B et al (2015) Increased arterial blood pressure and vascular remodeling in mice lacking salt-inducible kinase 1 (SIK1). Circ Res 116:642–652CrossRefPubMed
6.
Berdeaux R, Goebel N, Banaszynski L et al (2007) SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat Med 13:597–603CrossRefPubMed
7.
Cheng H, Liu P, Wang ZC et al (2009) SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal 2:ra35PubMedPubMedCentral
8.
9.
Horike N, Takemori H, Katoh Y et al (2003) Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem 278:18440–18447CrossRefPubMed
10.
Du J, Chen Q, Takemori H, Xu H (2008) SIK2 can be activated by deprivation of nutrition and it inhibits expression of lipogenic genes in adipocytes. Obesity 16:531–538CrossRefPubMed
11.
Gormand A, Berggreen C, Amar L et al (2014) LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues. J Mol Endocrinol 53:117–130CrossRefPubMed
12.
Katoh Y, Takemori H, Horike N et al (2004) Salt-inducible kinase (SIK) isoforms: their involvement in steroidogenesis and adipogenesis. Mol Cell Endocrinol 217:109–112CrossRefPubMed
13.
Patel K, Foretz M, Marion A et al (2014) The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun 5:4535CrossRefPubMedPubMedCentral
14.
Itoh Y, Sanosaka M, Fuchino H et al (2015) Salt inducible kinase 3 signaling is important for the gluconeogenic programs in mouse hepatocytes. J Biol Chem 209:17879–17893CrossRef
15.
Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R (2010) Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Investig 120:4316–4331CrossRefPubMedPubMedCentral
16.
Yoon YS, Seo WY, Lee MW, Kim ST, Koo SH (2009) Salt-inducible kinase regulates hepatic lipogenesis by controlling SREBP-1c phosphorylation. J Biol Chem 284:10446–10452CrossRefPubMedPubMedCentral
17.
18.
Dentin R, Liu Y, Koo SH et al (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449:366–369CrossRefPubMed
19.
20.
Park J, Yoon YS, Han HS et al (2014) SIK2 is critical in the regulation of lipid homeostasis and adipogenesis in vivo. Diabetes 63:3659–3673CrossRefPubMed
21.
Ko A, Cantor RM, Weissglas-Volkov D et al (2014) Amerindian-specific regions under positive selection harbour new lipid variants in Latinos. Nat Commun 5:3983CrossRefPubMedPubMedCentral
22.
Walkinshaw DR, Weist R, Kim GW et al (2013) The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases. J Biol Chem 288:9345–9362CrossRefPubMedPubMedCentral
23.
Clark K, MacKenzie KF, Petkevicius K et al (2012) Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc Natl Acad Sci U S A 109:16986–16991CrossRefPubMedPubMedCentral
24.
Screaton RA, Conkright MD, Katoh Y et al (2004) The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119:61–74CrossRefPubMed
25.
Henriksson E, Jones HA, Patel K et al (2012) The AMPK-related kinase SIK2 is regulated by cAMP via phosphorylation at Ser358 in adipocytes. Biochem J 444:503–514CrossRefPubMedPubMedCentral
26.
Berggreen C, Henriksson E, Jones HA, Morrice N, Goransson O (2012) cAMP-elevation mediated by beta-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes. Cell Signal 24:1863–1871CrossRefPubMed
27.
Pettersson AM, Stenson BM, Lorente-Cebrian S et al (2013) LXR is a negative regulator of glucose uptake in human adipocytes. Diabetologia 56:2044–2054CrossRefPubMed
28.
Andersson DP, Eriksson Hogling D, Thorell A et al (2014) Changes in subcutaneous fat cell volume and insulin sensitivity after weight loss. Diabetes Care 37:1831–1836CrossRefPubMed
29.
Kolaczynski JW, Morales LM, Moore JH Jr et al (1994) A new technique for biopsy of human abdominal fat under local anaesthesia with Lidocaine. Int J Obes Relat Metab Disord 18:161–166PubMed
30.
Andersson DP, Thorell A, Lofgren P et al (2014) Omentectomy in addition to gastric bypass surgery and influence on insulin sensitivity: a randomized double blind controlled trial. Clin Nutr 33:991–996CrossRefPubMed
31.
32.
Berggreen C, Gormand A, Omar B, Degerman E, Goransson O (2009) Protein kinase B activity is required for the effects of insulin on lipid metabolism in adipocytes. Am J Phys Endocrinol Metab 296:E635–E646CrossRef
33.
Pettersson AM, Acosta JR, Bjork C et al (2015) MAFB as a novel regulator of human adipose tissue inflammation. Diabetologia 58:2115–2123CrossRefPubMed
34.
Perez-Perez R, Lopez JA, Garcia-Santos E et al (2012) Uncovering suitable reference proteins for expression studies in human adipose tissue with relevance to obesity. PLoS One 7:e30326CrossRefPubMedPubMedCentral
35.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Investig 95:2409–2415CrossRefPubMedPubMedCentral
36.
37.
Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65CrossRefPubMed
38.
Watson RT, Pessin JE (2001) Subcellular compartmentalization and trafficking of the insulin-responsive glucose transporter, GLUT4. Exp Cell Res 271:75–83CrossRefPubMed
39.
Hajduch E, Litherland GJ, Hundal HS (2001) Protein kinase B (PKB/Akt) – a key regulator of glucose transport? FEBS Lett 492:199–203CrossRefPubMed
40.
Nixon M, Stewart-Fitzgibbon R, Fu J et al (2016) Skeletal muscle salt inducible kinase 1 promotes insulin resistance in obesity. Mol Metab 5:34–46CrossRefPubMed
Metadata
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
Authors
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
Publication date
01-02-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 2/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4141-y

Other articles of this Issue 2/2017

Diabetologia 2/2017 Go to the issue

Article

Adipocyte STAT5 deficiency promotes adiposity and impairs lipid mobilisation in mice

Article

ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

Article

The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet

Up front

Up front

Review

Glia: silent partners in energy homeostasis and obesity pathogenesis

Article

The cytoskeletal protein septin 11 is associated with human obesity and is involved in adipocyte lipid storage and metabolism
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits