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

• Published in: Journal of drug targeting Vol. 28; no. 7-8; pp. 831 - 851
• Main Authors: Crombez, Deborah, Delcambre, Sébastien, Nonclercq, Denis, Vander Elst, Luce, Laurent, Sophie, Cnop, Miriam, Muller, Robert N., Burtea, Carmen
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 13.09.2020
• Subjects: Adiponectin; adiponectin receptors; metabolic syndrome; obesity; peptide; type 2 diabetes; metabolic syndrome; peptide; type 2 diabetes; obesity; adiponectin receptors; Adiponectin
• ISSN: 1061-186X; 1029-2330; 1029-2330
• DOI: 10.1080/1061186X.2019.1710840

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.