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 3

LIPA disruption suppresses β-agonist-induced adipose lipolysis in cultured adipocytes and WAT explant.

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LIPA disruption suppresses β-agonist-induced adipose lipolysis in cultur...
(A) Schematic illustration of strategy to generate LIPA knockout primary adipocytes through differentiating the SV cells isolated from the iWAT of A-Lipa KO and control mice. (B) Confirmation of LIPA depletion at mRNA and (C) protein expression levels in Lipa KO adipocytes (n = 6). (D) Isoproterenol-induced lipolysis measured as glycerol and FFA release in supernatants from Lipa KO adipocytes (n = 6) or (E) lalistat-2–treated primary adipocytes (n = 3). (F) Glycerol and FFA levels of iWAT explant supernatant from A-Lipa KO versus control mice or (G) from lalistat-2– or vehicle-injected C57BL/6J mice treated with or without 1 μM isoproterenol at indicated time points (n = 4). All mice were male and fed an ND. Values are presented as mean ± SEM. Significant differences were determined by Student’s t test (B and C) or 2-way ANOVA with a post-hoc Tukey’s HSD test (D–G) for comparisons with the indicated groups (baseline groups: **P < 0.01; ***P < 0.001, or iso-treated groups: #P < 0.05; ##P < 0.01; ###P < 0.001). See also Supplemental Figure 11–15.