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 6

Adipocyte LIPA deficiency promotes the development of diet-induced obesity.

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Adipocyte LIPA deficiency promotes the development of diet-induced obesi...
(A) Experimental strategy outlining characterization of A-Lipa KO and control mice in response to diet-induced obesity with metabolic assays performed. (B) Body weight, (C) body composition, (D) adipose depot tissue weights, and (E) H&E-stained tissue sections of iWAT (left panel), eWAT (middle panel), and BAT (right panel) from A-Lipa KO and control mice after 16 weeks of HFD treatment (n = 15). Scale bars: 100 μm. (F) Oxygen consumption and (G) RER in A-Lipa KO and control mice 10 weeks into the HFD study (n = 5). (H) Glucose tolerance test and calculated area under the curve in A-Lipa KO and control mice assessed following 12 weeks of HFD (n = 10). (I) Insulin tolerance test and calculated area under the curve in A-Lipa KO and control mice assessed following 10 weeks of HFD (n = 9). All mice were male. Values are presented as mean ± SEM. Significant differences were determined by Student’s t test compared with ND groups: *P < 0.05; **P < 0.01; ***P < 0.001. See also Supplemental Figure 20.