[en] Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes.
Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization
by lipid droplet-associated proteins as well as lipolytic enzymes have been identified.
Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti-obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3-L1 adipocytes were characterized. Mitochondrial uncoupling-induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial uncoupling relies on a form of autophagy as lipid droplets are captured by endolysosomal vesicles. This new mechanism of triacylglycerol breakdown in adipocytes exposed to mild uncoupling provides new insights on the biology of adipocytes dealing with mitochondria forced to dissipate energy.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Demine, Stéphane
Tejerina, Silvia
Bihin, Benoît
Thiry, Marc ; Université de Liège > Département des sciences de la vie > GIGA-R : Biologie cellulaire
Reddy, Nagabushana
Renard, Patricia
Raes, Martine
Jadot, Michel
Arnould, Thierry
Language :
English
Title :
Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes
Publication date :
February 2018
Journal title :
Journal of Cellular Physiology
ISSN :
0021-9541
eISSN :
1097-4652
Publisher :
Wiley Liss, Inc., New York, United States - New York
Adler-Wailes, D. C., Alberobello, A. T., Ma, X., Hugendubler, L., Stern, E. A., Mou, Z., … Mueller, E. (2015). Analysis of variants and mutations in the human winged helix FOXA3 gene and associations with metabolic traits. International Journal of Obesity, 39(6), 888–892.
Adler, J., & Parmryd, I. (2010). Quantifying colocalization by correlation: The Pearson correlation coefficient is superior to the Mander's overlap coefficient. Cytometry Part A: The Journal of the International Society for Analytical Cytology, 77(8), 733–742.
Anthonsen, M. W., Ronnstrand, L., Wernstedt, C., Degerman, E., & Holm, C. (1998). Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. The Journal of Biological Chemistry, 273(1), 215–221.
Arner, P., Bernard, S., Salehpour, M., Possnert, G., Liebl, J., Steier, P., … Spalding, K. L. (2011). Dynamics of human adipose lipid turnover in health and metabolic disease. Nature, 478(7367), 110–113.
Bakker, E. P., Van den Heuvel, E. J., & Van Dam, K. (1974). The binding of uncouplers of oxidative phosphorylation to rat-liver mitochondria. Biochimica Et Biophysica Acta, 333(1), 12–21.
Bandyopadhyay, U., Kaushik, S., Varticovski, L., & Cuervo, A. M. (2008). The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Molecular and Cellular Biology, 28(18), 5747–5763.
Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., … Johansen, T. (2005). P62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of Cell Biology, 171(4), 603–614.
Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., … Guy-Grand, B. (1998). A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature, 392(6674), 398–401.
Cuervo, A. M., Dice, J. F., & Knecht, E. (1997). A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. The Journal of Biological Chemistry, 272(9), 5606–5615.
Dawaliby, R., & Mayer, A. (2010). Microautophagy of the nucleus coincides with a vacuolar diffusion barrier at nuclear-vacuolar junctions. Molecular Biology of the Cell, 21(23), 4173–4183.
DeCourcy, K., & Storrie, B. (1991). Osmotic swelling of endocytic compartments induced by internalized sucrose is restricted to mature lysosomes in cultured mammalian cells. Experimental Cell Research, 192(1), 52–60.
Delaive, E., Arnould, T., Raes, M., & Renard, P. (2008). A sensitive three-step protocol for fluorescence-based Western blot detection. Journal of Immunological Methods, 334(1-2), 51–58.
Demine, S., Michel, S., Vannuvel, K., Wanet, A., Renard, P., & Arnould, T. (2012). Macroautophagy and cell responses related to mitochondrial dysfunction, lipid metabolism and unconventional secretion of proteins. Cells, 1(2), 168–203.
De Pauw, A., Demine, S., Tejerina, S., Dieu, M., Delaive, E., Kel, A., … Arnould, T. (2012). Mild mitochondrial uncoupling does not affect mitochondrial biogenesis but downregulates pyruvate carboxylase in adipocytes: Role for triglyceride content reduction. American Journal of Physiology Endocrinology and Metabolism, 302(9), E1123–E1141.
Doco-Fenzy, M., Leroy, C., Schneider, A., Petit, F., Delrue, M. A., Andrieux, J., … Genevieve, D. (2014). Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes. European Journal of Human Genetics: EJHG, 22(4), 471–479.
Dunn, K. W., Kamocka, M. M, & McDonald, J. H. (2011). A practical guide to evaluating colocalization in biological microscopy. American Journal of Physiology Cell Physiology, 300(4), C723–C742.
Edens, N. K., Leibel, R. L., & Hirsch, J. (1990). Mechanism of free fatty acid re-esterification in human adipocytes in vitro. Journal of Lipid Research, 31(8), 1423–1431.
Fuller, K. M., & Arriaga, E. A. (2003). Analysis of individual acidic organelles by capillary electrophoresis with laser-induced fluorescence detection facilitated by the endocytosis of fluorescently labeled microspheres. Analytical Chemistry, 75(9), 2123–2130.
Furuchi, T., Aikawa, K., Arai, H., & Inoue, K. (1993). Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, blocks lysosomal cholesterol trafficking in macrophages. The Journal of Biological Chemistry, 268(36), 27345–27348.
Gilham, D., Ho, S., Rasouli, M., Martres, P., Vance, D. E., & Lehner, R. (2003). Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 17(12), 1685–1687.
Graham, J. M. (2002). Preparation of crude subcellular fractions by differential centrifugation. The Scientific World Journal, 2, 1638–1642.
Guh, D. P., Zhang, W., Bansback, N., Amarsi, Z., Birmingham, C. L., & Anis, A. H. (2009). The incidence of co-morbidities related to obesity and overweight: A systematic review and meta-analysis. BMC Public Health, 9, 88.
Hanada, T., Noda, N. N., Satomi, Y., Ichimura, Y., Fujioka, Y., Takao, T., … Ohsumi Y. (2007). The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. The Journal of Biological Chemistry, 282(52), 37298–37302.
Harper, J. A., Dickinson, K., & Brand, M. D. (2001). Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obesity Reviews: An Official Journal of the International Association for the Study of Obesity, 2(4), 255–265.
Hermoso, J., Pignol, D., Kerfelec, B., Crenon, I., Chapus, C., & Fontecilla-Camps, J. C. (1996). Lipase activation by nonionic detergents. The crystal structure of the porcine lipase-colipase-tetraethylene glycol monooctyl ether complex. The Journal of Biological Chemistry, 271(30), 18007–18016.
Hong, J., Nakano, Y., Yokomakura, A., Ishihara, K., Kim, S., Kang, Y. S., & Ohuchi, K. (2006). Nitric oxide production by the vacuolar-type (H+)-ATPase inhibitors bafilomycin A1 and concanamycin A and its possible role in apoptosis in RAW 264.7 cells. The Journal of Pharmacology and Experimental Therapeutics, 319(2), 672–681.
Hosogai, N., Fukuhara, A., Oshima, K., Miyata, Y., Tanaka, S., Segawa, K., … Shimomura, I. (2007). Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes, 56(4), 901–911.
Hubbard, V. M., Valdor, R, Patel, B., Singh, R., Cuervo, A. M., & Macian, F. (2010). Macroautophagy regulates energy metabolism during effector T cell activation. Journal of Immunology, 185(12), 7349–7357.
Jensen, M. D., Ekberg, K., & Landau, B. R. (2001). Lipid metabolism during fasting. American Journal of Physiology Endocrinology and Metabolism, 281(4), E789–E793.
Jones, L. R., Wilson, C. I., & Wadden, T. A. (2007). Lifestyle modification in the treatment of obesity: An educational challenge and opportunity. Clinical Pharmacology and Therapeutics, 81(5), 776–779.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., … Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. The EMBO Journal, 19(21), 5720–5728.
Kalinovich, A. V., & Shabalina, I. G. (2015). Novel mitochondrial cationic uncoupler C4R1 is an effective treatment for combating obesity in mice. Biochemistry Biokhimiia, 80(5), 620–628.
Kaushik, S., & Cuervo, A. M. (2015). Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nature Cell Biology, 17(6), 759–770.
Kaushik, S., & Cuervo, A. M. (2016). AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy, 12(2), 432–438.
Kaushik, S., Rodriguez-Navarro, J. A., Arias, E., Kiffin, R., Sahu, S., Schwartz, G. J., … Singh, R. (2011). Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metabolism, 14(2), 173–183.
Keipert, S., Ost, M., Johann, K., Imber, F., Jastroch, M., van Schothorst, E. M., … Klaus, S. (2014). Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. American Journal of Physiology Endocrinology and Metabolism, 306(5), E469–E482.
Kershaw, E. E., Schupp, M., Guan, H. P., Gardner, N. P., Lazar, M. A., & Flier, J. S. (2007). PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo. American Journal of Physiology Endocrinology and Metabolism, 293(6), E1736–E1745.
Kim, J. Y., Tillison, K., Lee, J. H., Rearick, D. A., & Smas, C. M. (2006). The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma. American Journal of Physiology Endocrinology and Metabolism, 291(1), E115–E127.
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., … Zughaier, S. M. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1–222.
Klionsky, D. J., Elazar, Z., Seglen, P. O., & Rubinsztein, D. C. (2008). Does bafilomycin A1 block the fusion of autophagosomes with lysosomes?. Autophagy, 4(7), 849–850.
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., … Chiba, T. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. The Journal of Cell Biology, 169(3), 425–434.
Kong, L. C., Holmes, B. A., Cotillard, A., Habi-Rachedi, F., Brazeilles, R., Gougis, S., … Clement, K. (2014). Dietary patterns differently associate with inflammation and gut microbiota in overweight and obese subjects. PLoS ONE, 9(10), e109434.
Kraft, C., Deplazes, A., Sohrmann, M., & Peter, M. (2008). Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nature Cell Biology, 10(5), 602–610.
Kunz, J. B., Schwarz, H., & Mayer, A. (2004). Determination of four sequential stages during microautophagy in vitro. The Journal of Biological Chemistry, 279(11), 9987–9996.
Lafontan, M., & Langin, D. (2009). Lipolysis and lipid mobilization in human adipose tissue. Progress in Lipid Research, 48(5), 275–297.
Lass, A., Zimmermann, R., Haemmerle, G., Riederer, M., Schoiswohl, G., Schweiger, M., … Zechner, R. (2006). Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metabolism, 3(5), 309–319.
Lass, A., Zimmermann, R., Oberer, M., & Zechner, R. (2011). Lipolysis−a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Progress in Lipid Research, 50(1), 14–27.
Lemasters, J. J. (2014). Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biology, 2, 749–754.
Lettieri Barbato, D., Tatulli, G., Aquilano, K., & Ciriolo, M. R. (2013). FoxO1 controls lysosomal acid lipase in adipocytes: Implication of lipophagy during nutrient restriction and metformin treatment. Cell Death & Disease, 4, e861.
Liu, L., Tao, Z., Zheng, L. D., Brooke, J. P., Smith, C. M., Liu, D., … Cheng, Z. (2016). FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes. Cell Death Discovery, 2, 16066.
Liu, L., Zheng, L. D., Zou, P., Brooke, J., Smith, C., Long, Y. C, … Cheng, Z. (2016). FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes. Cell Cycle, 15(15), 2033–2041.
Martinez-Lopez, N., Garcia-Macia, M., Sahu, S., Athonvarangkul, D., Liebling, E., Merlo, P., … Singh, R. (2016). Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metabolism, 23(1), 113–127.
Matejkova, O., Mustard, K. J., Sponarova, J., Flachs, P., Rossmeisl, M., Miksik, I., … Kopecky, J. (2004). Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat. FEBS Letters, 569(1-3), 245–248.
Maylie, M. F., Charles, M., & Desnuelle, P. (1972). Action of organophosphates and sulfonyl halides on porcine pancreatic lipase. Biochimica Et Biophysica Acta, 276(1), 162–175.
Montgomery, R. R., Webster, P., & Mellman, I. (1991). Accumulation of indigestible substances reduces fusion competence of macrophage lysosomes. Journal of Immunology, 147(9), 3087–3095.
Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., … Shimizu, S. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature, 461(7264), 654–658.
Pearson, G. L., Mellett, N., Chu, K. Y., Cantley, J., Davenport, A., Bourbon, P., … Biden, T. J. (2014). Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells. Diabetologia, 57(1), 129–139.
Pyo, J. O., Yoo, S. M., Ahn, H. H., Nah, J., Hong, S. H., Kam, T. I., … Jung, Y. K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Communications, 4, 2300.
Rambold, A. S., Cohen, S., & Lippincott-Schwartz, J. (2015). Fatty acid trafficking in starved cells: Regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Developmental Cell, 32(6):678–692.
Rider, M. H., Hussain, N., Dilworth, S. M., Storey, J. M., & Storey, K. B. (2011). AMP-activated protein kinase and metabolic regulation in cold-hardy insects. Journal of Insect Physiology, 57(11), 1453–1462.
Sahu-Osen, A., Montero-Moran, G., Schittmayer, M., Fritz, K., Dinh, A., Chang, Y. F., … Brasaemle, D. L. (2015). CGI-58/ABHD5 is phosphorylated on Ser239 by protein kinase A: Control of subcellular localization. Journal of Lipid Research, 56(1), 109–121.
Sakai, Y., Koller, A., Rangell, L. K., Keller, G. A., & Subramani, S. (1998). Peroxisome degradation by microautophagy in Pichia pastoris: Identification of specific steps and morphological intermediates. The Journal of Cell Biology, 141(3), 625–636.
Schimmel, R. J. (1976). Roles of alpha and beta adrenergic receptors in control of glucose oxidation in hamster epididymal adipocytes. Biochimica Et Biophysica Acta, 428(2), 379–387.
Senocak, F. S., Si, Y., Moya, C., Russell, W. K., Russell, D. H., Lee, K., & Jayaraman, A. (2007). Effect of uncoupling protein-1 expression on 3T3-L1 adipocyte gene expression. FEBS Letters, 581(30), 5865–5871.
Sewell, R. B., Barham, S. S., & LaRusso, N. F. (1983). Effect of chloroquine on the form and function of hepatocyte lysosomes. Morphologic modifications and physiologic alterations related to the biliary excretion of lipids and proteins. Gastroenterology, 85(5), 1146–1153.
Si, Y., Palani, S., Jayaraman, A., & Lee, K. (2007). Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism. Journal of Lipid Research, 48(4), 826–836.
Si, Y., Shi, H., & Lee, K. (2009). Metabolic flux analysis of mitochondrial uncoupling in 3T3-L1 adipocytes. PLoS ONE, 4(9), e7000.
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., … Czaja, M. J. (2009). Autophagy regulates lipid metabolism. Nature, 458(7242), 1131–1135.
Singh, R., Xiang, Y., Wang, Y., Baikati, K., Cuervo, A. M., Luu, Y. K., … Czaja, M. J. (2009). Autophagy regulates adipose mass and differentiation in mice. The Journal of Clinical Investigation, 119(11), 3329–3339.
Skop, V., Cahova, M., Dankova, H., Papackova, Z., Palenickova, E., Svoboda, P., … Kazdova, L. (2014). Autophagy inhibition in early but not in later stages prevents 3T3-L1 differentiation: Effect on mitochondrial remodeling. Differentiation; Research in Biological Diversity, 87(5), 220–229.
Souza, S. C., Muliro, K. V., Liscum, L., Lien, P., Yamamoto, M. T., Schaffer, J. E., … Greenberg, A. S. (2002). Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. The Journal of Biological Chemistry, 277(10), 8267–8272.
Spangenburg, E. E., Pratt, S. J., Wohlers, L. M., & Lovering, R. M. (2011). Use of BODIPY (493/503) to visualize intramuscular lipid droplets in skeletal muscle. Journal of Biomedicine & Biotechnology, 2011, 598358.
Sprinthall, R. C. (2012). Basic statistical analysis. Boston: Pearson Allyn & Bacon.
Sun, K., Kusminski, C. M., & Scherer, P. E. (2011). Adipose tissue remodeling and obesity. The Journal of Clinical Investigation, 121(6), 2094–2101.
Sun, R., Luo, Y., Li, J., Wang, Q., Li, J., Chen, X., … Yu, Z. (2015). Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 36(2), 1173–1177.
Tanida, I., Tanida-Miyake, E., Ueno, T., & Kominami, E. (2001). The human homolog of Saccharomyces cerevisiae Apg7p is a protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3. The Journal of Biological Chemistry, 276(3), 1701–1706.
Tansey, J. T., Huml, A. M., Vogt, R., Davis, K. E., Jones, J. M., Fraser, K. A., … Londos, C. (2003). Functional studies on native and mutated forms of perilipins. A role in protein kinase A-mediated lipolysis of triacylglycerols. The Journal of Biological Chemistry, 278(10), 8401–8406.
Tejerina, S., De Pauw, A., Vankoningsloo, S., Houbion, A., Renard, P., De Longueville, F., … Arnould, T. (2009). Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARgamma-independent mechanism, whereas TNFalpha-induced de-differentiation is PPARgamma dependent. Journal of Cell Science, 122(Pt 1), 145–155.
Teruel, T., Hernandez, R., Rial, E., Martin-Hidalgo, A., & Lorenzo, M. (2005). Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats. Diabetologia, 48(6), 1180–1188.
Thiam, A. R., Farese, R. V., Jr., Walther, T. C. (2013). The biophysics and cell biology of lipid droplets. Nature Reviews Molecular Cell Biology, 14(12), 775–786.
Tsuboyama, K., Koyama-Honda, I., Sakamaki, Y., Koike, M., Morishita, H., & Mizushima, N. (2016). The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science, 354(6315), 1036–1041.
Turner, N., Cooney, G. J., Kraegen, E. W., & Bruce, C. R. (2014). Fatty acid metabolism, energy expenditure and insulin resistance in muscle. The Journal of Endocrinology, 220(2), T61–T79.
Ueno, T., Ishidoh, K., Mineki, R., Tanida, I., Murayama, K., Kadowaki, M., & Kominami, E. (1999). Autolysosomal membrane-associated betaine homocysteine methyltransferase. Limited degradation fragment of a sequestered cytosolic enzyme monitoring autophagy. The Journal of Biological Chemistry, 274(21), 15222–15229.
Vankoningsloo, S., De Pauw, A., Houbion, A., Tejerina, S., Demazy, C., de Longueville, F., … Arnould, T. (2006). CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes. Journal of Cell Science, 119(Pt 7), 1266–1282.
Vankoningsloo, S., Piens, M., Lecocq, C., Gilson, A., De Pauw, A., Renard, P., … Arnould, T. (2005). Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: Role of fatty acid beta-oxidation and glucose. Journal of Lipid Research, 46(6), 1133–1149.
van Zutphen, T., Todde, V., de Boer, R., Kreim, M., Hofbauer, H. F., Wolinski, H., … Kohlwein, S. D. (2014). Lipid droplet autophagy in the yeast Saccharomyces cerevisiae. Molecular Biology of the Cell, 25(2), 290–301.
Wabitsch, M., Funcke, J. B., Lennerz, B., Kuhnle-Krahl, U., Lahr, G., Debatin, K. M., … Fischer-Posovszky, P. (2015). Biologically inactive leptin and early-onset extreme obesity. The New England Journal of Medicine, 372(1), 48–54.
Wang, C. W., Miao, Y. H., & Chang, Y. S. (2014). A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast. The Journal of Cell Biology, 206(3), 357–366.
Wang, Y., Nartiss, Y., Steipe, B., McQuibban, G. A., & Kim, P. K. (2012). ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy, 8(10), 1462–1476.
Watt, M. J., Holmes, A. G., Pinnamaneni, S. K., Garnham, A. P., Steinberg, G. R., Kemp, B. E., & Febbraio, M. A. (2006). Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. American Journal of Physiology Endocrinology and Metabolism, 290(3), E500–E508.
Wattiaux, R., Wattiaux-De Coninck, S., Ronveaux-dupal, M. F., & Dubois, F. (1978). Isolation of rat liver lysosomes by isopycnic centrifugation in a metrizamide gradient. The Journal of Cell Biology, 78(2), 349–368.
Wei, E., Gao, W., & Lehner, R. (2007). Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux. The Journal of Biological Chemistry, 282(11), 8027–8035.
Yamamoto, A., Tagawa, Y., Yoshimori, T., Moriyama, Y., Masaki, R., & Tashiro, Y. (1998). Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Structure and Function, 23(1), 33–42.
Yang, X., Zhang, X., Heckmann, B. L., Lu, X., & Liu, J. (2011). Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-alpha (TNF-alpha)-induced lipolysis in adipocytes. The Journal of Biological Chemistry, 286(47), 40477–40485.
Yin, J., Gao, Z., He, Q., Zhou, D., Guo, Z., & Ye, J. (2009). Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. American Journal of Physiology Endocrinology and Metabolism, 296(2), E333–E342.
Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M., & Tashiro, Y. (1991). Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. The Journal of Biological Chemistry, 266(26), 17707–17712.
Zhang, Y., Goldman, S., Baerga, R., Zhao, Y., Komatsu, M., & Jin, S. (2009). Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proceedings of the National Academy of Sciences of the United States of America, 106(47), 19860–19865.
Zhdanov, A. V., Dmitriev, R. I., & Papkovsky, D. B. (2011). Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria. Cellular and Molecular Life Sciences: CMLS, 68(5), 903–917.
Zhdanov, A. V., Dmitriev, R. I., & Papkovsky, D. B. (2012). Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling. Bioscience Reports, 32(6), 587–595.