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Article https://doi.org/10.1038/s41467-025-56613-3Non-canonical lysosomal lipolysis drivesmobilization of adipose tissue energy storeswith fastingGV Naveen Kumar 1 , Rui-Sheng Wang 2,3 , Ankit X. Sharma 1 , Natalie L. David 1,4,5 ,Tânia Amorim 1,4,5 , Daniel S. Sinden1,6 , Nandini K. Doshi 1 , Martin Wabitsch 7 ,Sebastien Gingras8 , Asim Ejaz 9 , J. Peter Rubin 9,10,11 , Bradley A. Maron 12,13 ,Pouneh K. Fazeli4,5& Matthew L. Steinhauser1,4,6Physiological adaptations to fasting enable humans to survive for prolongedperiods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization offatty acids and glycerol from adipocyte lipid stores by canonical neutral lipa-ses, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), iscritical to the adaptive fasting response. Here we discovered an alternativemechanism of lipolysis in adipocytes involving a lysosomal program. Wefunctionally tested lysosomal lipolysis with pharmacological and geneticapproaches in mice and in murine and human adipocyte and adipose tissueexplant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL)and the microphthalmia/transcription factor E (MiT/TFE) family. Our studyestablishesamodelwherebythecanonicalpathwayiscriticalforrapidlipolyticresponses to adrenergic stimuli operative in the acute stage of fasting, whilethe alternative lysosomal pathway dominates with prolonged fasting.The metabolic adaptation to fasting enables humans to survive formonths without exogenous energy intake 1,2 . However, the biology offasting may be relevant beyond starvation. Caloric restriction, includ-ing when achieved by intermittent fasting, prolongs life in modelorganisms ranging from yeast to mammals 3 . Yet, dysregulation ofpathways crucial to survival with starvation are maladaptive in othercontexts;indeed,whereaslipidstoredin adipocytes isa criticalenergysource during fasting, inappropriate lipolysis in obesity driveslipotoxicityandinsulinresistanceindistanttissuessuchastheliver 4 .Inshort, the tuning of adipocyte lipid turnover to systemic energy bal-ance is an important determinant of metabolic homeostasis.The canonical view of how adipocytes mobilize lipid storesinvokes the coordinated action of lipases, which release three fattyacid chains and one glycerol backbone from each triglyceridemolecule 5 . Adipocyte triglyceride lipase (ATGL) cleaves the f i rst fattyacid chain and is considered rate limiting, followed by hormoneReceived: 8 October 2024Accepted: 21 January 2025Check for updates1 AgingInstituteofUPMCandUniversityofPittsburghSchoolofMedicine,Pittsburgh,PA,USA. 2 DivisionofCardiovascularMedicine,DepartmentofMedicine,Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.3 Channing Division of Network Medicine, Department of Medicine, BrighamandWomen’sHospitalandHarvardMedicalSchool,Boston,MA,USA. 4 CenterforHumanIntegrativePhysiology,UniversityofPittsburghSchoolofMedicine,Pittsburgh, PA, USA.5 Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School ofMedicine, Pittsburgh, PA,USA.6 Division of Cardiology,Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA,USA. 7 UniversityMedicalCenterDepartmentofPediatricsandAdolescentMedicine,Ulm,Germany. 8 DepartmentofImmunology,UniversityofPittsburghSchoolofMedicine,Pittsburgh,PA,USA. 9 DepartmentofPlasticSurgery,University ofPittsburgh,Pittsburgh,PA15261,USA. 10 DepartmentofBioengineering,SwansonSchoolofEngineering, University of Pittsburgh, Pittsburgh, PA, USA.11 McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine,Pittsburgh, PA, USA.12 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. 13 The University of Maryland-Institute forHealth Computing, Bethesda, MD, USA. e-mail: msteinhauser@pitt.eduNature Communications| (2025) 16:1330 11234567890():,;1234567890():,;