Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis
Yu-Sheng Yeh, … , Irfan J. Lodhi, Babak Razani
Yu-Sheng Yeh, … , Irfan J. Lodhi, Babak Razani
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e185340. https://doi.org/10.1172/JCI185340.
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Research Article Endocrinology Metabolism

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

Abstract

Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.

Authors

Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani

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Figure 1

LIPA in adipocytes is stimulated by fasting, CE, and β-agonists.

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LIPA in adipocytes is stimulated by fasting, CE, and β-agonists. (A) Sch...
(A) Schematic illustration of cytosolic versus lysosomal lipolysis and key enzymes involved. (B) Experimental information and log2 fold changes of lipase gene expression in datasets (60–63) characterizing eWAT during fasting. (C) Gene expression of Lipa and cytosolic lipases and (D) protein expression of LIPA and ATGL (PNPLA2) in eWAT from mice fasted 16 hours (n = 3–4). (E) log2 Fold changes of Lipa and ATGL (Pnpla2) gene expression in datasets (64–68) examining CE or CL treatment. (F) Gene expression of Lipa and ATGL (Pnpla2) (n = 8) and (G) protein expression of LIPA and ATGL (PNPLA2) (n = 3–4) in iWAT from mice housed at 4ºC (left panel) or treated with CL (right panel) for 1 or 3 days. (H) Gene expression of Lipa and ATGL (Pnpla2) (n = 5–6) and (I) protein expression of LIPA and ATGL (PNPLA2) in differentiated primary adipocytes derived from iWAT SV cells treated with isoproterenol for indicted durations. (J) Gene expression of Lipa and ATGL (Pnpla2) (n = 4) and (K) protein expression of LIPA and ATGL (PNPLA2) in C3H1T1/2 adipocytes treated with isoproterenol for indicated durations. All mice were male and fed an ND. Values are presented as mean ± SEM. Significant differences were determined by Student’s t test (C, D, H, and J) or 1-way ANOVA with a post hoc Tukey’s HSD (F and G) for comparisons with the indicated groups. *P < 0.05; **P < 0.01; ***P < 0.001. See also associated Supplemental Figures 1–4.