Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting
Abstract Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56613-3 |
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| author | GV Naveen Kumar Rui-Sheng Wang Ankit X. Sharma Natalie L. David Tânia Amorim Daniel S. Sinden Nandini K. Doshi Martin Wabitsch Sebastien Gingras Asim Ejaz J. Peter Rubin Bradley A. Maron Pouneh K. Fazeli Matthew L. Steinhauser |
| author_facet | GV Naveen Kumar Rui-Sheng Wang Ankit X. Sharma Natalie L. David Tânia Amorim Daniel S. Sinden Nandini K. Doshi Martin Wabitsch Sebastien Gingras Asim Ejaz J. Peter Rubin Bradley A. Maron Pouneh K. Fazeli Matthew L. Steinhauser |
| author_sort | GV Naveen Kumar |
| collection | DOAJ |
| description | Abstract Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting. |
| format | Article |
| id | doaj-art-41137d4f709346e295c48bdcb7482b0d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-41137d4f709346e295c48bdcb7482b0d2025-02-09T12:44:04ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56613-3Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fastingGV Naveen Kumar0Rui-Sheng Wang1Ankit X. Sharma2Natalie L. David3Tânia Amorim4Daniel S. Sinden5Nandini K. Doshi6Martin Wabitsch7Sebastien Gingras8Asim Ejaz9J. Peter Rubin10Bradley A. Maron11Pouneh K. Fazeli12Matthew L. Steinhauser13Aging Institute of UPMC and University of Pittsburgh School of MedicineDivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolAging Institute of UPMC and University of Pittsburgh School of MedicineAging Institute of UPMC and University of Pittsburgh School of MedicineAging Institute of UPMC and University of Pittsburgh School of MedicineAging Institute of UPMC and University of Pittsburgh School of MedicineAging Institute of UPMC and University of Pittsburgh School of MedicineUniversity Medical Center Department of Pediatrics and Adolescent MedicineDepartment of Immunology, University of Pittsburgh School of MedicineDepartment of Plastic Surgery, University of PittsburghDepartment of Plastic Surgery, University of PittsburghDepartment of Medicine, University of Maryland School of MedicineCenter for Human Integrative Physiology, University of Pittsburgh School of MedicineAging Institute of UPMC and University of Pittsburgh School of MedicineAbstract Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.https://doi.org/10.1038/s41467-025-56613-3 |
| spellingShingle | GV Naveen Kumar Rui-Sheng Wang Ankit X. Sharma Natalie L. David Tânia Amorim Daniel S. Sinden Nandini K. Doshi Martin Wabitsch Sebastien Gingras Asim Ejaz J. Peter Rubin Bradley A. Maron Pouneh K. Fazeli Matthew L. Steinhauser Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting Nature Communications |
| title | Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| title_full | Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| title_fullStr | Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| title_full_unstemmed | Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| title_short | Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| title_sort | non canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting |
| url | https://doi.org/10.1038/s41467-025-56613-3 |
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