Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.

Summary

This mechanistic study shows that lysosomal acid lipase-driven lipolysis is upregulated during fasting, cold exposure, and β-adrenergic stimulation, and is essential for maintaining circulating FFAs, thermogenesis, and energy expenditure. Adipocyte LIPA deficiency impairs cold tolerance and increases susceptibility to diet-induced obesity, acting independently of cytosolic ATGL.

Key Findings

• Adipocyte LIPA expression increases during fasting, cold exposure, and β-adrenergic stimulation.
• Genetic or pharmacologic inhibition of LIPA lowers plasma FFAs under lipolytic conditions and impairs thermogenesis and oxygen consumption.
• Lysosomal lipolysis operates independently of ATGL and its deficiency predisposes mice to diet-induced obesity.

Clinical Implications

Targeting lysosomal lipolysis (e.g., modulating LIPA) could open new avenues for treating obesity, cold intolerance, and metabolic disorders, but safety must be carefully evaluated given its role in thermogenesis.

Limitations

• Preclinical mouse and cellular models; human translatability remains to be established.
• Molecular trafficking and regulation of lysosomal lipolysis across adipocyte subtypes not fully resolved.

Future Directions

Define LIPA regulation in human adipose depots, assess pharmacologic modulation in large animals/humans, and map interplay with cytosolic lipases under diverse metabolic states.