{"doi":"10.1016/j.jbc.2021.101444","title":"Monomethyl branched-chain fatty acids are critical for Caenorhabitis elegans survival in elevated glucose conditions","abstract":"The maintenance of optimal membrane composition under basal and stress conditions is critical for the survival of an organism. High-glucose stress has been shown to perturb membrane properties by decreasing membrane fluidity, and the membrane sensor PAQR-2 is required to restore membrane integrity. However, the mechanisms required to respond to elevated dietary glucose are not fully established. In this study, we used a 13C stable isotope-enriched diet and mass spectrometry to better understand the impact of glucose on fatty acid dynamics in the membrane of Caenorhabditis elegans. We found a novel role for monomethyl branched-chain fatty acids (mmBCFAs) in mediating the ability of the nematodes to survive conditions of elevated dietary glucose. This requirement of mmBCFAs is unique to glucose stress and was not observed when the nematode was fed elevated dietary saturated fatty acid. In addition, when worms deficient in elo-5, the major biosynthesis enzyme of mmBCFAs, were fed Bacillus subtilis (a bacteria strain rich in mmBCFAs) in combination with high glucose, their survival rates were rescued to wild-type levels. Finally, the results suggest that mmBCFAs are part of the PAQR-2 signaling response during glucose stress. Taken together, we have identified a novel role for mmBCFAs in stress response in nematodes and have established these fatty acids as critical for adapting to elevated glucose. The maintenance of optimal membrane composition under basal and stress conditions is critical for the survival of an organism. High-glucose stress has been shown to perturb membrane properties by decreasing membrane fluidity, and the membrane sensor PAQR-2 is required to restore membrane integrity. However, the mechanisms required to respond to elevated dietary glucose are not fully established. In this study, we used a 13C stable isotope-enriched diet and mass spectrometry to better understand the impact of glucose on fatty acid dynamics in the membrane of Caenorhabditis elegans. We found a novel role for monomethyl branched-chain fatty acids (mmBCFAs) in mediating the ability of the nematodes to survive conditions of elevated dietary glucose. This requirement of mmBCFAs is unique to glucose stress and was not observed when the nematode was fed elevated dietary saturated fatty acid. In addition, when worms deficient in elo-5, the major biosynthesis enzyme of mmBCFAs, were fed Bacillus subtilis (a bacteria strain rich in mmBCFAs) in combination with high glucose, their survival rates were rescued to wild-type levels. Finally, the results suggest that mmBCFAs are part of the PAQR-2 signaling response during glucose stress. Taken together, we have identified a novel role for mmBCFAs in stress response in nematodes and have established these fatty acids as critical for adapting to elevated glucose. In many disease states, including diabetes, cancer, and neurodegenerative diseases, defects in membrane structure and composition have been identified (1Gianfrancesco M.A. Paquot N. Piette J. Legrand-Poels S. Lipid bilayer stress in obesity-linked inflammatory and metabolic disorders.Biochem. Pharmacol. 2018; 153: 168-183Google Scholar, 2Pilon M. Revisiting the membrane-centric view of diabetes.Lipids Health Dis. 2016; 15: 167Google Scholar, 3Samuel V. Shulman G. Mechanisms for insulin resistance: Common threads and missing links.Cell (Cambridge). 2012; 148: 852-871Google Scholar, 4Bandu R. Mok H.J. Kim K.P. Phospholipids as cancer biomarkers: Mass spectrometry-based analysis.Mass Spectrom. Rev. 2018; 37: 107-138Google Scholar, 5Fanning S. Haque A. Imberdis T. Baru V. Barrasa M.I. Nuber S. Termine D. Ramalingam N. Ho G.P.H. Noble T. Sandoe J. Lou Y. Landgraf D. Freyzon Y. Newby G. et al.Lipidomic analysis of α-synuclein neurotoxicity identifies stearoyl CoA desaturase as a target for Parkinson treatment.Mol. Cell. 2019; 73: 1001-1014.e8Google Scholar, 6Fecchio C. Palazzi L. de Laureto P.P. A-synuclein and polyunsaturated fatty acids: Molecular ","journal":"Journal of Biological Chemistry","year":2021,"id":182388,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"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":735450,"name":"Mark A. Xatse","orcid":null,"position":1,"is_corresponding":false},{"id":735451,"name":"Hamide Tifeki","orcid":null,"position":2,"is_corresponding":false},{"id":552374,"name":"Cédric Diot","orcid":"0000-0003-2982-9392","position":3,"is_corresponding":false},{"id":305730,"name":"Albertha J.M. Walhout","orcid":"0000-0001-5587-3608","position":4,"is_corresponding":false},{"id":473692,"name":"Carissa Perez Olsen","orcid":"0000-0003-1261-9364","position":5,"is_corresponding":false},{"id":735449,"name":"Andre F.C. Vieira","orcid":null,"position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:48:13.605421Z","pmid":"34826420","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":[]}