{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:56:07Z","timestamp":1790877367348,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Cell Biology","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) is a central regulator of lipid metabolism and a critical mediator of neuroprotection, yet the mechanisms linking these functions remain unclear. Here, we identify the\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  nuclear receptor SEX-1 as a functional PPAR\u03b3-like regulator and define a pathway that coordinates lipid metabolism with mitochondrial homeostasis to preserve neuronal function. Integrating comparative genomics, multi-omics profiling, meta-analysis, and experimental validation, we show that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet (LD) dynamics, and mitochondrial quality control through interconnected lipogenic and autophagic programs. Loss of\n                  <jats:italic>sex-1<\/jats:italic>\n                  disrupts this metabolic network, resulting in aberrant LD accumulation, mitochondrial dysfunction, and widespread alterations in sphingolipid metabolism. These defects compromise the structural integrity and thermosensory function of amphid neurons during early adulthood, while the capacity of SEX-1 to restrict neuronal lipid droplet accumulation declines with age. Notably, genetic modulation of sphingolipid metabolic pathways rescues neuronal defects, establishing a causal link between lipid metabolic homeostasis and neuronal maintenance. Together, our findings identify a PPAR\u03b3-like signalling axis that integrates sphingolipid metabolism, organelle quality control, and neuronal homeostasis, providing a mechanistic framework for understanding how metabolic regulation promotes neuroprotection.\n                <\/jats:p>","DOI":"10.64898\/2026.09.28.755091","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:40:15Z","timestamp":1790703615000},"source":"Crossref","is-referenced-by-count":0,"title":["A PPAR\u03b3-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-8203","authenticated-orcid":false,"given":"Dikaia","family":"Tsagkari","sequence":"first","affiliation":[{"name":"Division of Basic Sciences, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece Figure"},{"name":"Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Markaki","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing, University Medical Centre Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands"},{"name":"College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Nollen","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing, University Medical Centre Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5253-1466","authenticated-orcid":false,"given":"Nektarios","family":"Tavernarakis","sequence":"additional","affiliation":[{"name":"Division of Basic Sciences, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece Figure"},{"name":"Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 70013, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100109550697000_2026.09.28.755091v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3214"},{"key":"2026100109550697000_2026.09.28.755091v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.018"},{"key":"2026100109550697000_2026.09.28.755091v1.3","doi-asserted-by":"crossref","unstructured":"An, L. , Fu, X. , Chen, J. & Ma, J . Application of Caenorhabditis elegans in Lipid Metabolism Research. Int J Mol Sci 24 (2023).","DOI":"10.3390\/ijms24021173"},{"key":"2026100109550697000_2026.09.28.755091v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/25931"},{"key":"2026100109550697000_2026.09.28.755091v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3159"},{"key":"2026100109550697000_2026.09.28.755091v1.6","first-page":"768594","article-title":"Role of PPAR gamma in the Differentiation and Function of Neurons","volume":"2014","year":"2014","journal-title":"PPAR Res"},{"key":"2026100109550697000_2026.09.28.755091v1.7","doi-asserted-by":"crossref","unstructured":"Iannotti, F.A. & Vitale, R.M . The Endocannabinoid System and PPARs: Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation. Cells 10 (2021).","DOI":"10.3390\/cells10030586"},{"key":"2026100109550697000_2026.09.28.755091v1.8","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s00441-017-2615-y","article-title":"PPARgamma activation regulates lipid droplet formation and lactate production in rat Sertoli cells","volume":"369","year":"2017","journal-title":"Cell Tissue Res"},{"key":"2026100109550697000_2026.09.28.755091v1.9","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R021006"},{"key":"2026100109550697000_2026.09.28.755091v1.10","doi-asserted-by":"crossref","first-page":"618322","DOI":"10.3389\/fcell.2020.618322","article-title":"Two Types of Contact Between Lipid Droplets and Mitochondria","volume":"8","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2026100109550697000_2026.09.28.755091v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0085-z"},{"key":"2026100109550697000_2026.09.28.755091v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36432-0"},{"key":"2026100109550697000_2026.09.28.755091v1.13","first-page":"435","article-title":"Lipid Droplets and the Management of Cellular Stress","volume":"92","year":"2019","journal-title":"Yale J Biol Med"},{"key":"2026100109550697000_2026.09.28.755091v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-011-1061-y"},{"key":"2026100109550697000_2026.09.28.755091v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.003"},{"key":"2026100109550697000_2026.09.28.755091v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112435"},{"key":"2026100109550697000_2026.09.28.755091v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10206"},{"key":"2026100109550697000_2026.09.28.755091v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2004.10.007"},{"key":"2026100109550697000_2026.09.28.755091v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2008.02.005"},{"key":"2026100109550697000_2026.09.28.755091v1.20","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12516"},{"key":"2026100109550697000_2026.09.28.755091v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002645"},{"key":"2026100109550697000_2026.09.28.755091v1.22","doi-asserted-by":"crossref","unstructured":"Leiteritz, A. , Baumanns, S. & Wenzel, U . Amyloid-beta (Abeta(1-42))-induced paralysis in Caenorhabditis elegans is reduced through NHR-49\/PPARalpha. Neurosci Lett 730, 135042 (2020).","DOI":"10.1016\/j.neulet.2020.135042"},{"key":"2026100109550697000_2026.09.28.755091v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/24164"},{"key":"2026100109550697000_2026.09.28.755091v1.24","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.107.078071"},{"key":"2026100109550697000_2026.09.28.755091v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-03819-2"},{"key":"2026100109550697000_2026.09.28.755091v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa443"},{"key":"2026100109550697000_2026.09.28.755091v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.08.001"},{"key":"2026100109550697000_2026.09.28.755091v1.28","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"2026100109550697000_2026.09.28.755091v1.29","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"},{"key":"2026100109550697000_2026.09.28.755091v1.30","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41419-022-04834-5","article-title":"An obesogenic feedforward loop involving PPARgamma, acyl-CoA binding protein and GABA(A) receptor","volume":"13","year":"2022","journal-title":"Cell Death Dis"},{"key":"2026100109550697000_2026.09.28.755091v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-024-07487-W"},{"key":"2026100109550697000_2026.09.28.755091v1.32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.mce.2017.07.037","article-title":"Differentially expressed genes in PPARgamma-deficient MSCs","volume":"471","year":"2018","journal-title":"Mol Cell Endocrinol"},{"key":"2026100109550697000_2026.09.28.755091v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111493"},{"key":"2026100109550697000_2026.09.28.755091v1.34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88894"},{"key":"2026100109550697000_2026.09.28.755091v1.35","doi-asserted-by":"crossref","first-page":"36937","DOI":"10.1038\/srep36937","article-title":"Intestinal PPARgamma signalling is required for sympathetic nervous system activation in response to caloric restriction","volume":"6","year":"2016","journal-title":"Sci Rep"},{"key":"2026100109550697000_2026.09.28.755091v1.36","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1038\/s42255-021-00493-6","article-title":"Lipolysis: cellular mechanisms for lipid mobilization from fat stores","volume":"3","year":"2021","journal-title":"Nat Metab"},{"key":"2026100109550697000_2026.09.28.755091v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-75502-x"},{"key":"2026100109550697000_2026.09.28.755091v1.38","doi-asserted-by":"crossref","unstructured":"Tracey, T.J. , Steyn, F.J. , Wolvetang, E.J. & Ngo, S.T . Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease. Front Mol Neurosci 11, 10 (2018).","DOI":"10.3389\/fnmol.2018.00010"},{"key":"2026100109550697000_2026.09.28.755091v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.10.002"},{"key":"2026100109550697000_2026.09.28.755091v1.40","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.016345"},{"key":"2026100109550697000_2026.09.28.755091v1.41","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glz067"},{"key":"2026100109550697000_2026.09.28.755091v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.06.035"},{"key":"2026100109550697000_2026.09.28.755091v1.43","doi-asserted-by":"crossref","first-page":"863907","DOI":"10.3389\/fcell.2022.863907","article-title":"Functions of Stress-Induced Lipid Droplets in the Nervous System","volume":"10","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"2026100109550697000_2026.09.28.755091v1.44","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1016\/j.bbamcr.2015.05.020","article-title":"Identification of lipid droplet structure-like\/resident proteins in Caenorhabditis elegans","volume":"1853","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"2026100109550697000_2026.09.28.755091v1.45","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202050214"},{"key":"2026100109550697000_2026.09.28.755091v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.09.045"},{"key":"2026100109550697000_2026.09.28.755091v1.47","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-020-02463-5"},{"key":"2026100109550697000_2026.09.28.755091v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/nature14300"},{"key":"2026100109550697000_2026.09.28.755091v1.49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.124164"},{"key":"2026100109550697000_2026.09.28.755091v1.50","doi-asserted-by":"crossref","unstructured":"Fu, L. et al. LET-767 determines lipid droplet protein targeting and lipid homeostasis. J Cell Biol 223 (2024).","DOI":"10.1083\/jcb.202311024"},{"key":"2026100109550697000_2026.09.28.755091v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELREP.2023.112902\/ATTACHMENT\/274C98DB-E771-47A2-B471-397B2AAAD1C1\/MMC12"},{"key":"2026100109550697000_2026.09.28.755091v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/376344a0"},{"key":"2026100109550697000_2026.09.28.755091v1.53","doi-asserted-by":"publisher","DOI":"10.1002\/neu.10245"},{"key":"2026100109550697000_2026.09.28.755091v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.02.023"},{"key":"2026100109550697000_2026.09.28.755091v1.55","doi-asserted-by":"crossref","unstructured":"Rosero, M. & Bai, J. AFD Thermosensory Neurons Mediate Tactile-Dependent Locomotion Modulation in C. elegans. bioRxiv (2025).","DOI":"10.7554\/eLife.106496.1"},{"key":"2026100109550697000_2026.09.28.755091v1.56","first-page":"1155","article-title":"The expanding role of sphingolipids in lipid droplet biogenesis","volume":"1862","year":"2017","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"2026100109550697000_2026.09.28.755091v1.57","doi-asserted-by":"crossref","first-page":"1302472","DOI":"10.3389\/fcell.2023.1302472","article-title":"Sphingolipids in mitochondria-from function to disease","volume":"11","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"2026100109550697000_2026.09.28.755091v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2022.03.011"},{"key":"2026100109550697000_2026.09.28.755091v1.59","doi-asserted-by":"crossref","first-page":"624112","DOI":"10.3389\/fendo.2021.624112","article-title":"PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action","volume":"12","year":"2021","journal-title":"Front Endocrinol (Lausanne"},{"key":"2026100109550697000_2026.09.28.755091v1.60","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201803153"},{"key":"2026100109550697000_2026.09.28.755091v1.61","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.freeradbiomed.2025.06.023","article-title":"PPARgamma mediated lysosomal membrane permeabilization and lipophagy blockage were involved in microplastics and di (2-ethylhexyl) phthalate co-exposure induced immature testis injury","volume":"237","year":"2025","journal-title":"Free Radic Biol Med"},{"key":"2026100109550697000_2026.09.28.755091v1.62","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03263-6"},{"key":"2026100109550697000_2026.09.28.755091v1.63","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0293OC"},{"key":"2026100109550697000_2026.09.28.755091v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12332-0"},{"key":"2026100109550697000_2026.09.28.755091v1.65","doi-asserted-by":"publisher","DOI":"10.1152\/advan.00052.2006"},{"key":"2026100109550697000_2026.09.28.755091v1.66","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13820"},{"key":"2026100109550697000_2026.09.28.755091v1.67","first-page":"835","article-title":"SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK","volume":"5","year":"2013","journal-title":"Aging (Albany NY"},{"key":"2026100109550697000_2026.09.28.755091v1.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.02.011"},{"key":"2026100109550697000_2026.09.28.755091v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.01.029"},{"key":"2026100109550697000_2026.09.28.755091v1.70","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27409"},{"key":"2026100109550697000_2026.09.28.755091v1.71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2009838117"},{"key":"2026100109550697000_2026.09.28.755091v1.72","doi-asserted-by":"crossref","unstructured":"Ralhan, I. , Chang, C.L. , Lippincott-Schwartz, J. & Ioannou, M.S . Lipid droplets in the nervous system. J Cell Biol 220 (2021).","DOI":"10.1083\/jcb.202102136"},{"key":"2026100109550697000_2026.09.28.755091v1.73","doi-asserted-by":"publisher","DOI":"10.1038\/35888"},{"key":"2026100109550697000_2026.09.28.755091v1.74","first-page":"270","article-title":"Lipid-lowering fibrates extend C. elegans lifespan in a NHR-49\/PPARalpha-dependent manner","volume":"5","year":"2013","journal-title":"Aging (Albany NY"},{"key":"2026100109550697000_2026.09.28.755091v1.75","doi-asserted-by":"crossref","first-page":"5859","DOI":"10.1007\/s00216-018-1200-x","article-title":"One- vs two-phase extraction: re-evaluation of sample preparation procedures for untargeted lipidomics in plasma samples","volume":"410","year":"2018","journal-title":"Anal Bioanal Chem"},{"key":"2026100109550697000_2026.09.28.755091v1.76","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D700041-JLR200"},{"key":"2026100109550697000_2026.09.28.755091v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.106"},{"key":"2026100109550697000_2026.09.28.755091v1.78","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp033"},{"key":"2026100109550697000_2026.09.28.755091v1.79","doi-asserted-by":"publisher","DOI":"10.1093\/MOLBEV\/MSAB120"},{"key":"2026100109550697000_2026.09.28.755091v1.80","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/8.3.275"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.28.755091","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:06:30Z","timestamp":1790874390000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.28.755091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":80,"URL":"https:\/\/doi.org\/10.64898\/2026.09.28.755091","relation":{},"subject":[],"published":{"date-parts":[[2026,9,29]]},"subtype":"preprint"}}