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Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting

Author

Listed:
  • GV Naveen Kumar

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine)

  • Rui-Sheng Wang

    (Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Ankit X. Sharma

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine)

  • Natalie L. David

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Tânia Amorim

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Daniel S. Sinden

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Nandini K. Doshi

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine)

  • Martin Wabitsch

    (University Medical Center Department of Pediatrics and Adolescent Medicine)

  • Sebastien Gingras

    (University of Pittsburgh School of Medicine)

  • Asim Ejaz

    (University of Pittsburgh)

  • J. Peter Rubin

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh School of Medicine)

  • Bradley A. Maron

    (University of Maryland School of Medicine
    The University of Maryland-Institute for Health Computing)

  • Pouneh K. Fazeli

    (University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Matthew L. Steinhauser

    (Aging Institute of UPMC and University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

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.

Suggested Citation

  • 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 , 2025. "Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56613-3
    DOI: 10.1038/s41467-025-56613-3
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