TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes

References

• Jebeile H, Kelly AS, O’Malley G, et al. Obesity in children and adolescents: epidemiology, causes, assessment, and management. Lancet Diabetes Endocrinol. 2022;10(5):351–365. doi: 10.1016/S2213-8587(22)00047-X
   PubMed Web of Science ®Google Scholar
• Daquinag AC, Tseng C, Salameh A, et al. Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development. Cell Death Differ. 2015;22(2):351–363. doi: 10.1038/cdd.2014.148
   PubMed Web of Science ®Google Scholar
• Oates EH, Antoniewicz MR. Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation. Metab Eng. 2022 69:221–230. doi: 10.1016/j.ymben.2021.12.005
   PubMed Web of Science ®Google Scholar
• Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011;12(11):722–734. doi: 10.1038/nrm3198
   PubMed Web of Science ®Google Scholar
• Grabner GF, Xie H, Schweiger M, et al. Lipolysis: cellular mechanisms for lipid mobilization from fat stores. Nat Metab. 2021;3(11):1445–1465. doi: 10.1038/s42255-021-00493-6
   PubMedGoogle Scholar
• Liu K, Czaja MJ. Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 2013;20(1):3–11. doi: 10.1038/cdd.2012.63
   PubMed Web of Science ®Google Scholar
• Gonzalez-Rodriguez P, Fullgrabe J, Joseph B. The hunger strikes back: an epigenetic memory for autophagy. Cell Death Differ. 2023;30(6):1404–1415. doi: 10.1038/s41418-023-01159-4
   PubMed Web of Science ®Google Scholar
• Pyo JO, Yoo SM, Ahn HH, et al. Overexpression of ATG5 in mice activates autophagy and extends lifespan. Nat Commun. 2013 4:2300. doi: 10.1038/ncomms3300
   PubMed Web of Science ®Google Scholar
• Yang L, Li P, Fu S, et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11(6):467–478. doi: 10.1016/j.cmet.2010.04.005
   PubMed Web of Science ®Google Scholar
• Heckmann BL, Yang X, Zhang X, et al. The autophagic inhibitor 3-methyladenine potently stimulates PKA-dependent lipolysis in adipocytes. Br J Pharmacol. 2013;168(1):163–171. doi: 10.1111/j.1476-5381.2012.02110.x
   PubMed Web of Science ®Google Scholar
• Cai J, Pires KM, Ferhat M, et al. autophagy ablation in adipocytes induces insulin resistance and reveals roles for lipid peroxide and Nrf2 signaling in adipose-liver crosstalk. Cell Rep. 2018;25(7):1708–1717 e5. doi: 10.1016/j.celrep.2018.10.040
   PubMed Web of Science ®Google Scholar
• Lee HY, Kim J, Quan W, et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy. 2016;12(8):1390–1403. doi: 10.1080/15548627.2016.1184799
   PubMed Web of Science ®Google Scholar
• Zhang T, Liu J, Shen S, et al. SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity. Cell Death Diff. 2020;27(1):329–344. doi: 10.1038/s41418-019-0356-z
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018;19(6):365–381. doi: 10.1038/s41580-018-0001-6
   PubMed Web of Science ®Google Scholar
• Tasset I, Cuervo AM. Role of chaperone-mediated autophagy in metabolism. FEBS J. 2016;283(13):2403–2413. doi: 10.1111/febs.13677
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol. 2015;17(6):759–770. doi: 10.1038/ncb3166
   PubMed Web of Science ®Google Scholar
• Madrigal-Matute J, de Bruijn J, van Kuijk K, et al. Protective role of chaperone-mediated autophagy against atherosclerosis. Proc Natl Acad Sci U S A. 2022;119(14):e2121133119. doi: 10.1073/pnas.2121133119
   PubMed Web of Science ®Google Scholar
• Tolosa E, Vila M, Klein C, et al. LRRK2 in parkinson disease: challenges of clinical trials. Nat Rev Neurol. 2020;16(2):97–107. doi: 10.1038/s41582-019-0301-2
   PubMed Web of Science ®Google Scholar
• Orenstein SJ, Kuo SH, Tasset I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 2013;16(4):394–406. doi: 10.1038/nn.3350
   PubMed Web of Science ®Google Scholar
• Rocha EM, Keeney MT, Di Maio R, et al. LRRK2 and idiopathic Parkinson’s disease. Trends Neurosci. 2022;45(3):224–236. doi: 10.1016/j.tins.2021.12.002
   PubMed Web of Science ®Google Scholar
• Alessi DR, Sammler E. LRRK2 kinase in Parkinson’s disease. Science. 2018;360(6384):36–37. doi: 10.1126/science.aar5683
   PubMed Web of Science ®Google Scholar
• Yue Z, Yang XW. Dangerous duet: LRRK2 and α-synuclein jam at CMA. Nat neurosci. 2013;16(4):375–377. doi: 10.1038/nn.3361
   PubMed Web of Science ®Google Scholar
• Ho PW, Leung CT, Liu H, et al. Age-dependent accumulation of oligomeric SNCA/alpha-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA). Autophagy. 2020;16(2):347–370. doi: 10.1080/15548627.2019.1603545
   PubMed Web of Science ®Google Scholar
• Chen CY, Weng YH, Chien KY, et al. (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ. 2012;19(10):1623–1633. doi: 10.1038/cdd.2012.42
   PubMed Web of Science ®Google Scholar
• Madureira M, Connor-Robson N, Wade-Martins R. LRRK2: autophagy and lysosomal activity. Front Neurosci. 2020; 14:498. doi: 10.3389/fnins.2020.00498
   PubMed Web of Science ®Google Scholar
• Albanese F, Mercatelli D, Finetti L, et al. Constitutive silencing of LRRK2 kinase activity leads to early glucocerebrosidase deregulation and late impairment of autophagy in vivo. Neurobiol Dis. 2021;159:105487. doi: 10.1016/j.nbd.2021.105487
   PubMed Web of Science ®Google Scholar
• Lin CW, Peng YJ, Lin YY, et al. LRRK2 regulates CPT1A to promote β-Oxidation in HepG2 Cells. Molecules. 2020;25(18):4122. doi: 10.3390/molecules25184122
   PubMed Web of Science ®Google Scholar
• Yu M, Arshad M, Wang W, et al. LRRK2 mediated Rab8a phosphorylation promotes lipid storage. Lipids Health Dis. 2018;17(1):34. doi: 10.1186/s12944-018-0684-x
   PubMedGoogle Scholar
• Hatano T, Kubo S, Imai S, et al. Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet. 2007;16(6):678–690. doi: 10.1093/hmg/ddm013
   PubMed Web of Science ®Google Scholar
• Seol W, Nam D, Son I. Rab GTPases as physiological substrates of LRRK2 kinase. Exp Neurobiol. 2019;28(2):134–145. doi: 10.5607/en.2019.28.2.134
   PubMed Web of Science ®Google Scholar
• Eguchi T, Kuwahara T, Sakurai M, et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Nat Acad Sci. 2018;115(39):E9115–E9124. doi: 10.1073/pnas.1812196115
   PubMed Web of Science ®Google Scholar
• Dodson MW, Zhang T, Jiang C, et al. Roles of the drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet. 2012;21(6):1350–1363. doi: 10.1093/hmg/ddr573
   PubMed Web of Science ®Google Scholar
• Kjos I, Borg Distefano M, Saetre F, et al. RAB7B modulates autophagic flux by interacting with Atg4B. EMBO Rep. 2017;18(10):1727–1739. doi: 10.15252/embr.201744069
   PubMed Web of Science ®Google Scholar
• Geng J, Yuan X, Wei M, et al. The diverse role of TIGAR in cellular homeostasis and cancer. Free Radic Res. 2018;52(11–12):1240–1249. doi: 10.1080/10715762.2018.1489133
   PubMed Web of Science ®Google Scholar
• Bensaad K, Cheung EC, Vousden KH. Modulation of intracellular ROS levels by TIGAR controls autophagy. Embo J. 2009;28(19):3015–3026. doi: 10.1038/emboj.2009.242
   PubMed Web of Science ®Google Scholar
• Zhang DM, Zhang T, Wang MM, et al. TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury. Free Radic Biol Med. 2019; 137:13–23. doi: 10.1016/j.freeradbiomed.2019.04.002
   PubMed Web of Science ®Google Scholar
• Hildebrandt X, Ibrahim M, Peltzer N. Cell death and inflammation during obesity: “Know my methods, WAT(son)”. Cell Death Differ. 2023;30(2):279–292.
   PubMed Web of Science ®Google Scholar
• Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007;87(2):507–520. doi: 10.1152/physrev.00024.2006
   PubMed Web of Science ®Google Scholar
• Schroeder B, Schulze RJ, Weller SG, et al. The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. Hepatology. 2015;61(6):1896–1907. doi: 10.1002/hep.27667
   PubMed Web of Science ®Google Scholar
• Ness D, Ren Z, Gardai S, et al. Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS One. 2013;8(6):e66164. doi: 10.1371/journal.pone.0066164
   PubMed Web of Science ®Google Scholar
• Lei Y, Klionsky DJ. Transcriptional regulation of autophagy and its implications in human disease. Cell Death Differ. 2023;30(6):1416–1429. doi: 10.1038/s41418-023-01162-9
   PubMed Web of Science ®Google Scholar
• Manzoni C, Mamais A, Dihanich S, et al. Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta. 2013;1833(12):2900–2910. doi: 10.1016/j.bbamcr.2013.07.020
   PubMed Web of Science ®Google Scholar
• Qiao L, Wang HF, Xiang L, et al. Deficient chaperone-mediated autophagy promotes lipid accumulation in macrophage. J Cardiovasc Transl Res. 2021;14(4):661–669. doi: 10.1007/s12265-020-09986-3
   PubMed Web of Science ®Google Scholar
• Cantalupo G, Alifano P, Roberti V, et al. Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. Embo J. 2001;20(4):683–693. doi: 10.1093/emboj/20.4.683
   PubMed Web of Science ®Google Scholar
• Ding X, Goldberg MS, Cookson MR. Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP. PloS One. 2009;4(6):e5949. doi: 10.1371/journal.pone.0005949
   PubMed Web of Science ®Google Scholar
• Yang Y, Klionsky DJ. Autophagy and disease: unanswered questions. Cell Death Differ. 2020;27(3):858–871. doi: 10.1038/s41418-019-0480-9
   PubMed Web of Science ®Google Scholar
• Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell. 2015;32(6):678–692. doi: 10.1016/j.devcel.2015.01.029
   PubMed Web of Science ®Google Scholar
• Li Y, Chao X, Yang L, et al. Impaired fasting-induced adaptive lipid droplet biogenesis in liver-specific ATG5-deficient mouse liver Is mediated by persistent nuclear factor-like 2 activation. Am J Pathol. 2018;188(8):1833–1846. doi: 10.1016/j.ajpath.2018.04.015
   PubMed Web of Science ®Google Scholar
• Cheung EC, DeNicola GM, Nixon C, et al. Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell. 2020;37(2):168–182 e4. doi: 10.1016/j.ccell.2019.12.012
   PubMed Web of Science ®Google Scholar
• Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A. 2012;109(50):20491–20496. doi: 10.1073/pnas.1206530109
   PubMed Web of Science ®Google Scholar
• Xie JM, Li B, Yu HP, et al. TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy. Cancer Res. 2014;74(18):5127–5138. doi: 10.1158/0008-5472.CAN-13-3517
   PubMed Web of Science ®Google Scholar
• Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):531–543. doi: 10.1016/S0092-8674(01)00240-9
   PubMed Web of Science ®Google Scholar
• Guyenet SJ, Schwartz MW. Clinical review: regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab. 2012;97(3):745–755. doi: 10.1210/jc.2011-2525
   PubMed Web of Science ®Google Scholar
• Leibold S, Bagivalu Lakshminarasimha A, Gremse F, et al. Long-term obesogenic diet leads to metabolic phenotypes which are not exacerbated by catch-up growth in zebrafish. PLoS One. 2022;17(5):e0267933. doi: 10.1371/journal.pone.0267933
   PubMed Web of Science ®Google Scholar
• Blaak EE, Goossens GH. Metabolic phenotyping in people living with obesity: implications for dietary prevention. Rev Endocr Metab Disord. 2023;24(5):825–838. doi: 10.1007/s11154-023-09830-4
   PubMed Web of Science ®Google Scholar
• Cifuentes L, Ghusn W, Feris F, et al. Phenotype tailored lifestyle intervention on weight loss and cardiometabolic risk factors in adults with obesity: a single-centre, non-randomised, proof-of-concept study. EClinicalMedicine. 2023;58:101923. doi: 10.1016/j.eclinm.2023.101923
   PubMedGoogle Scholar
• Inada K, Tsujimoto K, Yoshida M, et al. (2022). Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice. Elife, 11:e75718. doi: 10.7554/eLife.75718
   PubMed Web of Science ®Google Scholar
• Deblon N, Veyrat-Durebex C, Bourgoin L, et al. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One. 2011;6(9):e25565. doi: 10.1371/journal.pone.0025565
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy. 2016;12(2):432–438. doi: 10.1080/15548627.2015.1124226
   PubMed Web of Science ®Google Scholar
• Greenberg AS, Coleman RA, Kraemer FB, et al. The role of lipid droplets in metabolic disease in rodents and humans. J Clin Invest. 2011;121(6):2102–2110. doi: 10.1172/JCI46069
   PubMed Web of Science ®Google Scholar
• Itabe H, Yamaguchi T, Nimura S, et al. Perilipins: a diversity of intracellular lipid droplet proteins. Lipids Health Dis. 2017;16(1):83. doi: 10.1186/s12944-017-0473-y
   PubMedGoogle Scholar
• Beller M, Bulankina AV, Hsiao HH, et al. PERILIPIN-dependent control of lipid droplet structure and fat storage in Drosophila. Cell Metab. 2010;12(5):521–532. doi: 10.1016/j.cmet.2010.10.001
   PubMed Web of Science ®Google Scholar
• Zhang T, Liu J, Tong Q, et al. SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. Int J Mol Sci. 2020;21(2):372. doi: 10.3390/ijms21020372
   PubMed Web of Science ®Google Scholar
• Zhang T, Fang Z, Linghu KG, et al. Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes. Br J Pharmacol. 2020;177(20):4645–4665. doi: 10.1111/bph.15215
   PubMed Web of Science ®Google Scholar
• Shen S, Liao Q, Zhang T, et al. Myricanol modulates skeletal muscle-adipose tissue crosstalk to alleviate high-fat diet-induced obesity and insulin resistance. Br J Pharmacol. 2019;176(20):3983–4001. doi: 10.1111/bph.14802
   PubMed Web of Science ®Google Scholar
• Peralta ER, Martin BC, Edinger AL. Differential effects of TBC1D15 and mammalian Vps39 on Rab7 activation state, lysosomal morphology, and growth factor dependence. J Biol Chem. 2010;285(22):16814–16821. doi: 10.1074/jbc.M110.111633
   PubMed Web of Science ®Google Scholar
• Yang L, Gao Y, Gong J, et al. Myricetin ameliorated prediabetes via immunomodulation and gut microbiota interaction. Food Front. 2022;3(4):749–772. doi: 10.1002/fft2.152
   Google Scholar
• Liu J, Li D, Zhang T, et al. SIRT3 protects hepatocytes from oxidative injury by enhancing ROS scavenging and mitochondrial integrity. Cell Death Dis. 2017;8(10):e3158. doi: 10.1038/cddis.2017.564
   PubMed Web of Science ®Google Scholar
• Chen J, Zhang DM, Feng X, et al. (2018). TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes. Neuropharmacology, 131:377–388. doi: 10.1016/j.neuropharm.2018.01.012
   PubMed Web of Science ®Google Scholar
• Jeon YG, Lee JH, Ji Y, et al. RNF20 functions as a transcriptional coactivator for pparγ by promoting ncor1 degradation in adipocytes. Diabetes. 2020;69(1):20–34. doi: 10.2337/db19-0508
   PubMed Web of Science ®Google Scholar
• Linghu KG, Xiong SH, Zhao GD, et al. (2020). Sigesbeckia orientalis l. extract alleviated the collagen type ii-induced arthritis through inhibiting multi-target-mediated synovial hyperplasia and inflammation. Front Pharmacol, 11:547913. doi: 10.3389/fphar.2020.547913
   PubMed Web of Science ®Google Scholar
• Salihovic S, Broeckling CD, Ganna A, et al. Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes. Sci Rep. 2020;10(1):16474. doi: 10.1038/s41598-020-72456-y
   PubMed Web of Science ®Google Scholar
• Zhou Y, Liu L, Jin B, et al. Metrnl alleviates lipid accumulation by modulating mitochondrial homeostasis in diabetic nephropathy. Diabetes. 2023;72(5):611–626. doi: 10.2337/db22-0680
   PubMed Web of Science ®Google Scholar