{"doi":"10.1016/j.jlr.2021.100095","title":"PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions","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.","journal":"Journal of Lipid Research","year":2021,"id":172621,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348348,"name":"Ebrahim H. Ghazvini Zadeh","orcid":"0000-0001-5109-2417","position":1,"is_corresponding":false},{"id":497716,"name":"Peng Xu","orcid":"0000-0002-9593-7167","position":2,"is_corresponding":false},{"id":275030,"name":"Ruth Gordillo","orcid":"0000-0001-6533-2493","position":3,"is_corresponding":false},{"id":708943,"name":"Zheng Guo","orcid":"0000-0002-2294-3873","position":4,"is_corresponding":false},{"id":616309,"name":"Nolwenn Joffin","orcid":"0000-0003-2574-2089","position":5,"is_corresponding":false},{"id":497718,"name":"Biao Yu","orcid":"0000-0002-3607-578X","position":6,"is_corresponding":false},{"id":275031,"name":"Philipp E. Scherer","orcid":"0000-0003-0680-3392","position":7,"is_corresponding":false},{"id":702611,"name":"Wenhong Li","orcid":"0000-0003-4838-9695","position":8,"is_corresponding":false},{"id":638469,"name":"Toshiharu Onodera","orcid":"0000-0002-4439-0077","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:41.424716Z","pmid":"34214600","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}