PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions

Toshiharu Onodera, Ebrahim Ghazvini Zadeh, Peng Xu, Ruth Gordillo, Zheng Guo, Nolwenn Joffin, Biao Yu, Philipp E. Scherer, Wen Hong Li

Research output: Contribution to journalArticlepeer-review

Abstract

The pleiotropic actions of adiponectin in improving cell survival and metabolism have motivated the development of small-molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of the adiponectin receptors, yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic β-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high-fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared with AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.

Original languageEnglish (US)
Article number100095
JournalJournal of lipid research
Volume62
DOIs
StatePublished - Jun 1 2021

Keywords

  • Adiponectin
  • Ceramides
  • Diabetes
  • Drug optimization
  • Drug therapy/hypolipidemic drugs
  • High-fat diet
  • INS-1 beta cells
  • Insulin resistance
  • Lipid metabolism
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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