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Diabetologia

, Volume 61, Issue 9, pp 2054–2065 | Cite as

The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes

  • Tina Hörbelt
  • Christopher Tacke
  • Mariya Markova
  • Daniella Herzfeld de Wiza
  • Frederique Van de Velde
  • Marlies Bekaert
  • Yves Van Nieuwenhove
  • Silke Hornemann
  • Maria Rödiger
  • Nicole Seebeck
  • Elisabeth Friedl
  • Wenke Jonas
  • G. Hege Thoresen
  • Oliver Kuss
  • Anke Rosenthal
  • Volker Lange
  • Andreas F. H. Pfeiffer
  • Annette Schürmann
  • Bruno Lapauw
  • Natalia Rudovich
  • Olga Pivovarova
  • D. Margriet Ouwens
Article

Abstract

Aims/hypothesis

Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP1) has been recently identified as a proinflammatory adipokine. We examined whether WISP1 expression and circulating levels are altered in type 2 diabetes and whether WISP1 affects insulin signalling in muscle cells and hepatocytes.

Methods

Serum and visceral adipose tissue (VAT) biopsies, for analysis of circulating WISP1 levels by ELISA and WISP1 mRNA expression by real-time quantitative RT-PCR, were collected from normal-weight men (control group, n = 33) and obese men with (n = 46) and without type 2 diabetes (n = 56) undergoing surgery. Following incubation of primary human skeletal muscle cells (hSkMCs) and murine AML12 hepatocytes with WISP1 and insulin, insulin signalling was analysed by western blotting. The effect of WISP1 on insulin-stimulated glycogen synthesis and gluconeogenesis was investigated in hSkMCs and murine hepatocytes, respectively.

Results

Circulating WISP1 levels were higher in obese men (independent of diabetes status) than in normal-weight men (mean [95% CI]: 70.8 [55.2, 86.4] ng/l vs 42.6 [28.5, 56.6] ng/l, respectively; p < 0.05). VAT WISP1 expression was 1.9-fold higher in obese men vs normal-weight men (p < 0.05). Circulating WISP1 levels were positively associated with blood glucose in the OGTT and circulating haem oxygenase-1 and negatively associated with adiponectin levels. In hSkMCs and AML12 hepatocytes, recombinant WISP1 impaired insulin action by inhibiting phosphorylation of insulin receptor, Akt and its substrates glycogen synthase kinase 3β, FOXO1 and p70S6 kinase, and inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes.

Conclusions/interpretation

Circulating WISP1 levels and WISP1 expression in VAT are increased in obesity independent of glycaemic status. Furthermore, WISP1 impaired insulin signalling in muscle and liver cells.

Keywords

Adipokine Akt Insulin action Insulin resistance Type 2 diabetes Visceral adipose tissue WISP1 

Abbreviations

CRP

C-reactive protein

FOXO1

Forkhead box O1

GSK3β

Glycogen synthase kinase 3β

HO-1

Haem oxygenase-1

hSkMC

Human skeletal muscle cell

IRβ

Insulin receptor β

LRP

LDL receptor-related protein

MCP-1

Monocyte chemotactic protein 1

p70S6K

p70 S6 kinase

SAT

Subcutaneous adipose tissue

sFRP

Secreted frizzled-related protein

VAT

Visceral adipose tissue

Wnt

Wingless-type

WISP1

Wnt-inducible signalling protein-1

Notes

Acknowledgements

Part of this work was presented as an abstract at the 52nd European Association for the Study of Diabetes (EASD) Annual Meeting 2016.

Contribution statement

TH, NR, OP and DMO designed the study, conducted experiments, performed data analysis and drafted the manuscript. CT, MM, WJ, AFHP, SH, AR, VL, GHT and AS conducted experiments, performed data analysis and drafted the manuscript. DHdW, MR, NS and EF conducted experiments, performed data analysis and reviewed the manuscript. FVdV and MB collected clinical samples, analysed clinical data, maintained participants records, supervised clinical chemistry and reviewed the manuscript. YVN and BL designed and supervised the clinical study and reviewed the manuscript. OK performed statistical analysis and reviewed the manuscript. DMO and OP are the guarantors of this work, had full access to all the data and take full responsibility for the integrity of the data and the accuracy of the data analysis. All authors have seen and approved the final version of the manuscript.

Funding

This work was financially supported by a grant to NR and DMO from the German Center for Diabetes Research (‘WISP1 is a novel target for regulation of glucose metabolism’), by a grant to NR and DMO from European Foundation for Study of Diabetes (EFSD/AZ Cellular Plasticity, ‘Unravelling the role of WISP1 on metabolic and cellular plasticity in white adipose tissue’) and by an internal grant of the German Institute of Human Nutrition to MM (2017, ‘Effects of dietary protein intake on lipid metabolism and inflammatory markers in human adipose tissue’).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4636_MOESM1_ESM.pdf (1.3 mb)
ESM (PDF 1345 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Tina Hörbelt
    • 1
    • 2
  • Christopher Tacke
    • 2
    • 3
    • 4
  • Mariya Markova
    • 2
    • 3
  • Daniella Herzfeld de Wiza
    • 1
    • 2
  • Frederique Van de Velde
    • 5
  • Marlies Bekaert
    • 5
  • Yves Van Nieuwenhove
    • 6
  • Silke Hornemann
    • 2
    • 3
  • Maria Rödiger
    • 2
    • 7
  • Nicole Seebeck
    • 2
    • 3
  • Elisabeth Friedl
    • 3
  • Wenke Jonas
    • 2
    • 7
  • G. Hege Thoresen
    • 8
    • 9
  • Oliver Kuss
    • 2
    • 10
  • Anke Rosenthal
    • 11
  • Volker Lange
    • 12
    • 13
  • Andreas F. H. Pfeiffer
    • 2
    • 3
    • 4
  • Annette Schürmann
    • 2
    • 7
  • Bruno Lapauw
    • 5
  • Natalia Rudovich
    • 2
    • 3
    • 4
    • 14
  • Olga Pivovarova
    • 2
    • 3
    • 4
  • D. Margriet Ouwens
    • 1
    • 2
    • 5
  1. 1.Institute for Biochemistry and Pathobiochemistry, German Diabetes CenterDüsseldorfGermany
  2. 2.German Center for Diabetes Research (DZD)Muenchen-NeuherbergGermany
  3. 3.Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-RehbrueckeNuthetalGermany
  4. 4.Department of Endocrinology, Diabetes and NutritionCharité University MedicineBerlinGermany
  5. 5.Department of EndocrinologyGhent University HospitalGhentBelgium
  6. 6.Department of SurgeryGhent University HospitalGhentBelgium
  7. 7.Department of Experimental DiabetologyGerman Institute of Human NutritionPotsdamGermany
  8. 8.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway
  9. 9.Department of Pharmacology, Institute of Clinical MedicineUniversity of OsloOsloNorway
  10. 10.Institute for Biometrics and Epidemiology, German Diabetes CenterDuesseldorfGermany
  11. 11.Clinic for Nutritional MedicineBerlinGermany
  12. 12.Center for Obesity and Metabolic Surgery, Vivantes HospitalBerlinGermany
  13. 13.Helios Hospital Berlin-BuchBerlinGermany
  14. 14.Division of Endocrinology and Diabetology, Department of Internal MedicineSpital BülachBülachSwitzerland

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