Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis
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
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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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 5

Adipocyte LIPA is associated with obesity and affects adipose tissue morphology.

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Adipocyte LIPA is associated with obesity and affects adipose tissue mor...
(A) Study information and log2 fold changes of lipase gene expression in indicated study datasets (22, 69–72) profiling eWAT from models of obesity including mice or rats fed high-fat high sugar diet (HFHSD) or HFD or those which were genetically predisposed (ob/ob model). (B) Gene expression of lipases in eWAT from ND- or HFD-fed mice (n = 10 or 8). (C) Lipa gene expression in adipocyte fractions isolated from eWAT of ND- or HFD-fed mice (n = 5 or 6). (D) Correlations between Lipa expression in eWAT and body weight (left panel), fat mass (middle panel), or eWAT weight (right panel) among ND and HFD-fed mice. (E) Experimental strategy outlining characterization of adipose tissue in A-Lipa KO and control mice. (F) Adipose tissue weight (n = 10 and 11) and (G) H&E-stained tissue sections of iWAT (top panel), eWAT (middle panel), and BAT (bottom panel) with (H) quantification of adipocyte size (n = 6) from A-Lipa KO and control mice at 16 weeks of age. Scale bars: 20 μm. All mice were male. Values are presented as mean ± SEM. Significant differences were determined by Student’s t test compared with control or ND groups: *P < 0.05; **P < 0.01; ***P < 0.001. The correlation (r square) and P value were calculated by Pearson’s r test. See also Supplemental Figures 17–19.