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

doi:10.1016/j.jlr.2021.100095

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.

Highlights

AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides
More recent data showed that adiponectin was essential to maintain minimal lipid homeostasis under insulinopenic conditions to improve local lipid metabolism in the islets [14] and the process acts as an important antilipotoxic phenomenon to boost β-cell regeneration primarily mediated by adiponectin's action, at least in part, on the β-cells directly [15]
To assess the mechanism by which AdipoRonPEG5 improved insulin sensitivity or exerted adiponectin-like effects in vivo, we evaluated the expression of adiponectin-regulated genes in the pancreas, brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT) of mice on high-fat diet (HFD)

Summary

Introduction

AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. 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. More recent data showed that adiponectin was essential to maintain minimal lipid homeostasis under insulinopenic conditions to improve local lipid metabolism in the islets [14] and the process acts as an important antilipotoxic phenomenon to boost β-cell regeneration primarily mediated by adiponectin's action, at least in part, on the β-cells directly [15]. This is consistent with the direct action of adiponectin on β-cells as both AdipoR1 and AdipoR2 are abundantly expressed in islet β-cells [16, 17]

Methods

Results

Conclusion