Tina Hörbelt1,2, Christopher Tacke2,3,4, Mariya Markova2,3, Daniella Herzfeld de Wiza1,2, Frederique Van de Velde5, Marlies Bekaert5, Yves Van Nieuwenhove6, Silke Hornemann2,3, Maria Rödiger2,7, Nicole Seebeck2,3, Elisabeth Friedl3, Wenke Jonas2,7, G Hege Thoresen8,9, Oliver Kuss2,10, Anke Rosenthal11, Volker Lange12,13, Andreas F H Pfeiffer2,3,4, Annette Schürmann2,7, Bruno Lapauw5, Natalia Rudovich2,3,4,14, Olga Pivovarova15,16,17, D Margriet Ouwens1,2,5. 1. Institute for Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany. 2. German Center for Diabetes Research (DZD), Muenchen-Neuherberg, Germany. 3. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. 4. Department of Endocrinology, Diabetes and Nutrition, Charité University Medicine, Berlin, Germany. 5. Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. 6. Department of Surgery, Ghent University Hospital, Ghent, Belgium. 7. Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam, Germany. 8. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 9. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 10. Institute for Biometrics and Epidemiology, German Diabetes Center, Duesseldorf, Germany. 11. Clinic for Nutritional Medicine, Berlin, Germany. 12. Center for Obesity and Metabolic Surgery, Vivantes Hospital, Berlin, Germany. 13. Helios Hospital Berlin-Buch, Berlin, Germany. 14. Division of Endocrinology and Diabetology, Department of Internal Medicine, Spital Bülach, Bülach, Switzerland. 15. German Center for Diabetes Research (DZD), Muenchen-Neuherberg, Germany. Olga.Pivovarova@dife.de. 16. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. Olga.Pivovarova@dife.de. 17. Department of Endocrinology, Diabetes and Nutrition, Charité University Medicine, Berlin, Germany. Olga.Pivovarova@dife.de.
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.
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 obesemen 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 obesemen (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 obesemen 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 WISP1impaired 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, WISP1impaired insulin signalling in muscle and liver cells.
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