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

Summary

This study identifies a lysosomal lipolysis program in adipocytes that depends on LAL (LIPA) and MiT/TFE transcription factors and predominates during prolonged fasting, whereas canonical neutral lipases (e.g., ATGL) dominate acute adrenergic responses. The mechanism was demonstrated using pharmacologic and genetic perturbations in mice and in murine/human adipocyte and adipose explants.

Key Findings

• Identified a lysosomal lipolysis program in adipocytes that depends on LAL (LIPA) and MiT/TFE transcription factors.
• Demonstrated with pharmacologic/genetic tools in mice and murine/human adipocyte and adipose explant cultures.
• Proposed a model where canonical neutral lipases dominate acute fasting, while lysosomal lipolysis dominates prolonged fasting.

Clinical Implications

Although preclinical, targeting the MiT/TFE–LAL axis could modulate fasting responses, adiposity, and metabolic disease; biomarkers of lysosomal lipolysis may inform dietary or pharmacologic interventions.

Limitations

• Predominantly preclinical with no human in vivo clinical outcome data
• Metabolic consequences beyond lipolysis flux (e.g., glycemia, energy expenditure) not fully characterized in humans

Future Directions

Test pharmacologic activators/inhibitors of MiT/TFE–LAL in metabolic disease models and quantify lysosomal lipolysis in humans under fasting or dietary interventions.