The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes
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.
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.
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.
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.
KeywordsAdipokine Akt Insulin action Insulin resistance Type 2 diabetes Visceral adipose tissue WISP1
Forkhead box O1
Glycogen synthase kinase 3β
Human skeletal muscle cell
Insulin receptor β
LDL receptor-related protein
Monocyte chemotactic protein 1
p70 S6 kinase
Subcutaneous adipose tissue
Secreted frizzled-related protein
Visceral adipose tissue
Wnt-inducible signalling protein-1
Part of this work was presented as an abstract at the 52nd European Association for the Study of Diabetes (EASD) Annual Meeting 2016.
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.
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.
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