Modulation of adiponectin receptors AdipoR1 and AdipoR2 by phage display-derived peptides in in vitro and in vivo models

Abstract

Type 2 diabetes (T2D) is often linked to metabolic syndrome, which assembles various risk factors related to obesity. Plasma levels of adiponectin are decreased in T2D and obese subjects. Aiming to develop a peptide able to bind adiponectin receptors and modulate their signalling pathways, a 12-amino acid sequence homologous in AdipoR1/R2 has been targeted by phage display with a linear 12-mer peptide library. The selected peptide P17 recognises AdipoR1/R2 expressed by skeletal muscle, liver and pancreatic islets. In HepaRG and C2C12 cells, P17 induced the activation of AMPK (AMPKα-pT172) and the expression of succinate dehydrogenase and glucokinase; no cytotoxic effects were observed on HepaRG cells. In db/db mice, P17 promoted body weight and glycaemia stabilisation, decreased plasma triglycerides to the range of healthy mice and increased adiponectin (in high fat-fed mice) and insulin (in chow-fed mice) levels. It restored to the range of healthy mice the tissue levels and subcellular distribution of AdipoR1/R2, AMPKα-pT172 and PPARα-pS12. In liver, P17 reduced steatosis and apoptosis. The docking of P17 to AdipoR is reminiscent of the binding mechanism of adiponectin. To conclude, we have developed an AdipoR1/AdipoR2-targeted peptide that modulates adiponectin signalling pathways and has therapeutic relevance for T2D and obesity associated pathologies.

Keywords:

• Adiponectin
• adiponectin receptors
• peptide
• type 2 diabetes
• metabolic syndrome
• obesity

Acknowledgements

Mrs Marguerite Gillemon is gratefully acknowledged for generous financial donation. Prof Isabelle Salmon and Dr Sandrine Rorive from the Pathology Department of the Erasme Hospital, ULB (Brussels, Belgium) are gratefully acknowledged for kindly providing the sections of human pancreas, and Prof Celso Matos from the Champalimaud Clinical Centre (Lisbon, Portugal) for the careful perusal of the manuscript. Ms Françoise Coulon is gratefully acknowledged for her help with histology techniques. The authors thank the Centre for Microscopy and Molecular Imaging (CMMI, supported by the European Regional Development Fund and the Federation Wallonia Brussels). The peptides described in this article are the subject of a patent deposited by the University of Mons.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was funded by the UMONS-50 PhD fellowship of D.C. and the Funds for Medical Research in Hainaut (FRMH, Fonds pour la Recherche Médicale dans le Hainaut).