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

Naveen Kumar Gv, 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 and Matthew L. Steinhauser ()
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Naveen Kumar Gv: Aging Institute of UPMC and University of Pittsburgh School of Medicine
Rui-Sheng Wang: 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
Tânia Amorim: Aging Institute of UPMC and University of Pittsburgh School of Medicine
Daniel S. Sinden: Aging Institute of UPMC and 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
Bradley A. Maron: University of Maryland School of Medicine
Pouneh K. Fazeli: University of Pittsburgh School of Medicine
Matthew L. Steinhauser: Aging Institute of UPMC and University of Pittsburgh School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56613-3

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