{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:03:46Z","timestamp":1790143426137,"version":"4.0.1"},"reference-count":139,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,9,24]],"date-time":"2018-09-24T00:00:00Z","timestamp":1537747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal upregulation or downregulation of autophagy has been depicted as an attribute of a variety of pathologic conditions. In this review, we will describe the current knowledge on the role of autophagy, from its regulation to its physiological influence, in metabolic age-related disorders. Finally, we propose to discuss the therapeutic potential of pharmacological and nutritional modulators of autophagy to treat metabolic diseases.<\/jats:p>","DOI":"10.3390\/cells7100149","type":"journal-article","created":{"date-parts":[[2018,9,24]],"date-time":"2018-09-24T10:38:49Z","timestamp":1537785529000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Autophagy in Metabolic Age-Related Human Diseases"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0334-4584","authenticated-orcid":false,"given":"Manon","family":"Moulis","sequence":"first","affiliation":[{"name":"INSERM, UMR-1048, Institute of Cardiovascular and Metabolic Diseases and University Paul Sabatier; F-31342 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecile","family":"Vindis","sequence":"additional","affiliation":[{"name":"INSERM, UMR-1048, Institute of Cardiovascular and Metabolic Diseases and University Paul Sabatier; F-31342 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/scientificamerican0563-64","article-title":"The lysosome","volume":"208","year":"1963","journal-title":"Sci. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1152\/physrev.00030.2009","article-title":"Regulation of mammalian autophagy in physiology and pathophysiology","volume":"90","author":"Ravikumar","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cr.2013.168","article-title":"The machinery of macroautophagy","volume":"24","author":"Feng","year":"2014","journal-title":"Cell Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0014-5793(94)00672-5","article-title":"Isolation of autophagocytosis mutants of saccharomyces cerevisiae","volume":"349","author":"Thumm","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17621","DOI":"10.1074\/jbc.271.30.17621","article-title":"Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway","volume":"271","author":"Harding","year":"1996","journal-title":"J. Biol Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0014-5793(93)80398-E","article-title":"Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae","volume":"333","author":"Tsukada","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1534-5807(03)00296-X","article-title":"A unified nomenclature for yeast autophagy-related genes","volume":"5","author":"Klionsky","year":"2003","journal-title":"Dev. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-cellbio-092910-154005","article-title":"The role of Atg proteins in autophagosome formation","volume":"27","author":"Mizushima","year":"2011","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/ncb2078","article-title":"Plasma membrane contributes to the formation of pre-autophagosomal structures","volume":"12","author":"Ravikumar","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-59745-157-4_4","article-title":"LC3 and Autophagy","volume":"445","author":"Tanida","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1083\/jcb.200507002","article-title":"p62\/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death","volume":"171","author":"Lamark","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.4161\/auto.7.11.17166","article-title":"TFEB regulates autophagy: An integrated coordination of cellular degradation and recycling processes","volume":"7","author":"Settembre","year":"2011","journal-title":"Autophagy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1101\/gad.1599207","article-title":"Autophagy: Process and function","volume":"21","author":"Mizushima","year":"2007","journal-title":"Genes Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1210\/me.2014-1367","article-title":"Minireview: Autophagy in pancreatic \u03b2-cells and its implication in diabetes","volume":"29","author":"Watada","year":"2015","journal-title":"Mol. Endocrinol. Baltim. Md."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1007\/s00125-016-3868-9","article-title":"Autophagy is a major regulator of beta cell insulin homeostasis","volume":"59","author":"Riahi","year":"2016","journal-title":"Diabetologia"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hayes, H.L., Peterson, B.S., Haldeman, J.M., Newgard, C.B., Hohmeier, H.E., and Stephens, S.B. (2017). Delayed apoptosis allows islet \u03b2-cells to implement an autophagic mechanism to promote cell survival. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172567"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.cmet.2008.08.013","article-title":"Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia","volume":"8","author":"Jung","year":"2008","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16014","DOI":"10.1038\/ncomms16014","article-title":"Loss of mTORC1 signalling impairs \u03b2-cell homeostasis and insulin processing","volume":"8","author":"Barbaresso","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.2337\/db13-0970","article-title":"Pancreatic \u03b2-cell failure mediated by mTORC1 hyperactivity and autophagic impairment","volume":"63","author":"Asahara","year":"2014","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.cmet.2008.08.009","article-title":"Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet","volume":"8","author":"Ebato","year":"2008","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bernales, S., McDonald, K.L., and Walter, P. (2006). Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol., 4.","DOI":"10.1371\/journal.pbio.0040423"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9220","DOI":"10.1128\/MCB.01453-06","article-title":"Autophagy is activated for cell survival after endoplasmic reticulum stress","volume":"26","author":"Ogata","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"44746","DOI":"10.1038\/srep44746","article-title":"The endoplasmic reticulum stress\/autophagy pathway is involved in cholesterol-induced pancreatic \u03b2-cell injury","volume":"7","author":"Kong","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"42351","DOI":"10.1074\/jbc.R400019200","article-title":"Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes","volume":"279","author":"Robertson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"605","DOI":"10.2337\/db13-0909","article-title":"Nrf2 protects pancreatic \u03b2-cells from oxidative and nitrosative stress in diabetic model mice","volume":"63","author":"Yagishita","year":"2014","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22576","DOI":"10.1074\/jbc.M110.118976","article-title":"p62\/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription","volume":"285","author":"Jain","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1080\/15548627.2016.1208889","article-title":"Transcription factor NFE2L2\/NRF2 is a regulator of macroautophagy genes","volume":"12","author":"Pajares","year":"2016","journal-title":"Autophagy"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.tcb.2007.07.009","article-title":"ROS, mitochondria and the regulation of autophagy","volume":"17","author":"Elazar","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.mce.2013.09.031","article-title":"The PARK2 gene is involved in the maintenance of pancreatic \u03b2-cell functions related to insulin production and secretion","volume":"382","author":"Jin","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90693","DOI":"10.18632\/oncotarget.20963","article-title":"Inhibition of Miro1 disturbs mitophagy and pancreatic \u03b2-cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1126\/science.aaa2628","article-title":"Insulin granules. Insulin secretory granules control autophagy in pancreatic \u03b2 cells","volume":"347","author":"Goginashvili","year":"2015","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1210\/en.2017-03273","article-title":"\u03b2-Cell Autophagy in Diabetes Pathogenesis","volume":"159","author":"Marasco","year":"2018","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Martino, L., Masini, M., Novelli, M., Beffy, P., Bugliani, M., Marselli, L., Masiello, P., Marchetti, P., and De Tata, V. (2012). Palmitate activates autophagy in INS-1E \u03b2-cells and in isolated rat and human pancreatic islets. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036188"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.bbrc.2016.11.093","article-title":"Autophagy protects against cholesterol-induced apoptosis in pancreatic \u03b2-cells","volume":"482","author":"Wu","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"569","DOI":"10.3803\/EnM.2015.30.4.569","article-title":"Omega-3 polyunsaturated fatty acids may attenuate streptozotocin-induced pancreatic \u03b2-cell death via autophagy activation in fat1 transgenic mice","volume":"30","author":"Hwang","year":"2015","journal-title":"Endocrinol. Metab. (Seoul)"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.3892\/mmr.2016.5531","article-title":"Vitamin D induces autophagy of pancreatic \u03b2-cells and enhances insulin secretion","volume":"14","author":"Wang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.2337\/db16-1009","article-title":"Glucagon-like peptide 1 protects pancreatic \u03b2-cells from death by increasing autophagic flux and restoring lysosomal function","volume":"66","author":"Zummo","year":"2017","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.3892\/mmr.2015.3944","article-title":"Liraglutide protects pancreatic \u03b2-cells against free fatty acids in vitro and affects glucolipid metabolism in apolipoprotein E-\/- mice by activating autophagy","volume":"12","author":"Wang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29921","DOI":"10.1038\/srep29921","article-title":"Effect of exendin-4 on autophagy clearance in beta cell of rats with tacrolimus-induced diabetes mellitus","volume":"6","author":"Lim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.bbrc.2016.01.116","article-title":"Dipeptidyl peptidase-4 inhibitor MK-626 restores insulin secretion through enhancing autophagy in high fat diet-induced mice","volume":"470","author":"Liu","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1172\/JCI69625","article-title":"Amyloidogenic peptide oligomer accumulation in autophagy-deficient \u03b2 cells induces diabetes","volume":"124","author":"Kim","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1051\/bmdcn\/2017070201","article-title":"Autophagy and its link to type II diabetes mellitus","volume":"7","author":"Yang","year":"2017","journal-title":"BioMedicine"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.1074\/jbc.M114.605345","article-title":"Inhibition of autophagic turnover in \u03b2-cells by fatty acids and glucose leads to apoptotic cell death","volume":"290","author":"Mir","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1083\/jcb.201511042","article-title":"Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity","volume":"214","author":"Trudeau","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1038\/ncomms5934","article-title":"Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes","volume":"5","author":"Lim","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1007\/s00125-011-2350-y","article-title":"Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice","volume":"55","author":"Quan","year":"2012","journal-title":"Diabetologia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16348","DOI":"10.1038\/s41598-017-16485-0","article-title":"Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet","volume":"7","author":"Sheng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1007\/s00125-015-3665-x","article-title":"High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice","volume":"58","author":"Chu","year":"2015","journal-title":"Diabetologia"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1038\/ncomms3300","article-title":"Overexpression of Atg5 in mice activates autophagy and extends lifespan","volume":"4","author":"Pyo","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.1172\/JCI69866","article-title":"Human IAPP-induced pancreatic \u03b2 cell toxicity and its regulation by autophagy","volume":"124","author":"Shigihara","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1172\/JCI71981","article-title":"Autophagy defends pancreatic \u03b2 cells from human islet amyloid polypeptide-induced toxicity","volume":"124","author":"Rivera","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2798269","DOI":"10.1155\/2016\/2798269","article-title":"Islet amyloid polypeptide: Structure, function, and pathophysiology","volume":"2016","author":"Akter","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1042\/BCJ20160822","article-title":"Amino acid homeostasis and signalling in mammalian cells and organisms","volume":"474","year":"2017","journal-title":"Biochem. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nrendo.2014.35","article-title":"Autophagy\u2014A key player in cellular and body metabolism","volume":"10","author":"Kim","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.cell.2012.02.044","article-title":"Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway","volume":"149","author":"Han","year":"2012","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.molcel.2011.06.038","article-title":"p62 is a key regulator of nutrient sensing in the mTORC1 pathway","volume":"44","author":"Duran","year":"2011","journal-title":"Mol. Cell."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1074\/jbc.M116.772194","article-title":"General Control Nonderepressible 2 (GCN2) Kinase Inhibits Target of Rapamycin Complex 1 in Response to Amino Acid Starvation in Saccharomyces cerevisiae","volume":"292","author":"Yuan","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41574-018-0009-1","article-title":"Targeting autophagy in obesity: From pathophysiology to management","volume":"14","author":"Zhang","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1161\/CIRCRESAHA.110.227371","article-title":"Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes","volume":"107","author":"Hariharan","year":"2010","journal-title":"Circ. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrm3293","article-title":"Sirtuins as regulators of metabolism and healthspan","volume":"13","author":"Houtkooper","year":"2012","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_63","first-page":"3052","article-title":"Altered lipid content inhibits autophagic vesicular fusion","volume":"24","author":"Koga","year":"2010","journal-title":"FASEB J. Off Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.bbrc.2010.09.101","article-title":"Free fatty acids stimulate autophagy in pancreatic \u03b2-cells via JNK pathway","volume":"401","author":"Komiya","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"14364","DOI":"10.1074\/jbc.M111.294157","article-title":"Induction of autophagy by palmitic acid via protein kinase C-mediated signaling pathway independent of mTOR (mammalian target of rapamycin)","volume":"287","author":"Tan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1080\/15548627.2017.1359451","article-title":"Lipid droplets and lipotoxicity during autophagy","volume":"13","author":"Nguyen","year":"2017","journal-title":"Autophagy"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1159\/000343983","article-title":"Autophagy in adipose tissue","volume":"5","author":"Maixner","year":"2012","journal-title":"Obes. Facts"},{"key":"ref_68","first-page":"270","article-title":"Transcriptional Dysregulation of Adipose Tissue Autophagy in Obesity","volume":"31","author":"Maixner","year":"2016","journal-title":"Physiol. Bethesda Md."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/ijo.2013.27","article-title":"Defective regulation of adipose tissue autophagy in obesity","volume":"37","author":"Rodrigues","year":"2013","journal-title":"Int. J. Obes."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.arr.2016.10.005","article-title":"Impact of intermittent fasting on health and disease processes","volume":"39","author":"Mattson","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.metabol.2017.12.007","article-title":"Nutrient excess and autophagic deficiency: Explaining metabolic diseases in obesity","volume":"82","author":"Loos","year":"2018","journal-title":"Metabolism"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1001\/jama.2016.6190","article-title":"The Unrelenting Challenge of Obesity","volume":"315","author":"Zylke","year":"2016","journal-title":"JAMA"},{"key":"ref_73","first-page":"3","article-title":"Autophagy dysregulation and obesity-associated pathologies","volume":"41","author":"Namkoong","year":"2018","journal-title":"Mol. Cells"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.molmed.2007.04.002","article-title":"mTOR Complex1-S6K1 signaling: At the crossroads of obesity, diabetes and cancer","volume":"13","author":"Dann","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.cmet.2010.04.005","article-title":"Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance","volume":"11","author":"Yang","year":"2010","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1210\/en.2012-1625","article-title":"Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression","volume":"153","author":"Jansen","year":"2012","journal-title":"Endocrinology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2119\/molmed.2010.00023","article-title":"Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes","volume":"16","author":"Ost","year":"2010","journal-title":"Mol. Med. Camb. Mass."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.mce.2015.03.015","article-title":"Autophagy in adipose tissue of patients with obesity and type 2 diabetes","volume":"409","author":"Kosacka","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"43475","DOI":"10.1038\/srep43475","article-title":"Diet-induced obesity impairs spermatogenesis: A potential role for autophagy","volume":"7","author":"Mu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1080\/15548627.2016.1184799","article-title":"Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis","volume":"12","author":"Lee","year":"2016","journal-title":"Autophagy"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1210\/en.2011-1882","article-title":"Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response","volume":"153","author":"Quan","year":"2012","journal-title":"Endocrinology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nature18014","article-title":"AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy","volume":"534","author":"Shin","year":"2016","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/s41366-018-0030-4","article-title":"ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: Role of CaM kinase II.; histone H3K9 methyltransferase SUV39H.; Sirt1.; and PGC-1\u03b1 deacetylation","volume":"42","author":"Wang","year":"2018","journal-title":"Int. J. Obes."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1083\/jcb.12.1.198","article-title":"Cytoplasmic components in hepatic cell lysosomes","volume":"12","author":"Ashford","year":"1962","journal-title":"J. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7652","DOI":"10.1016\/S0021-9258(19)69010-1","article-title":"Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver","volume":"256","author":"Schworer","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1073\/pnas.80.8.2179","article-title":"Quantitative correlation between proteolysis and macro- and microautophagy in mouse hepatocytes during starvation and refeeding","volume":"80","author":"Mortimore","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1073\/pnas.76.7.3169","article-title":"Glucagon-induced autophagy and proteolysis in rat liver: Mediation by selective deprivation of intracellular amino acids","volume":"76","author":"Schworer","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nature07976","article-title":"Autophagy regulates lipid metabolism","volume":"458","author":"Singh","year":"2009","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1002\/hep.27667","article-title":"The small GTPase Rab7 as a central regulator of hepatocellular lipophagy","volume":"61","author":"Schroeder","year":"2015","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1002\/1873-3468.13203","article-title":"Upstream stimulating factor 1 suppresses autophagy and hepatic lipid droplet catabolism by activating mTOR","volume":"592","author":"Guo","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/ncb3166","article-title":"Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis","volume":"17","author":"Kaushik","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1083\/jcb.200412022","article-title":"Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice","volume":"169","author":"Komatsu","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"31484","DOI":"10.1074\/jbc.M109.033936","article-title":"Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: Inhibition of FoxO1-dependent expression of key autophagy genes by insulin","volume":"284","author":"Liu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e1179","DOI":"10.1038\/cddis.2014.162","article-title":"Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD","volume":"5","author":"Mayoral","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1002\/hep.28820","article-title":"Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice","volume":"64","author":"Tanaka","year":"2016","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nrgastro.2016.185","article-title":"Autophagy in the liver: Functions in health and disease","volume":"14","author":"Ueno","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cmet.2014.06.009","article-title":"Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation","volume":"20","author":"Schneider","year":"2014","journal-title":"Cell Metab."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1080\/15548627.2017.1356977","article-title":"Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition","volume":"13","author":"Kim","year":"2017","journal-title":"Autophagy"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1016\/j.jhep.2016.06.029","article-title":"Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy","volume":"65","author":"Lin","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1038\/nm.3288","article-title":"Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor","volume":"19","author":"Torisu","year":"2013","journal-title":"Nat. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1007\/s10439-014-1033-5","article-title":"Autophagy regulates vascular endothelial cell eNOS and ET-1 expression induced by laminar shear stress in an ex vivo perfused system","volume":"42","author":"Guo","year":"2014","journal-title":"Ann. Biomed. Eng."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1089\/dna.2015.3041","article-title":"Laminar Shear Stress Promotes Vascular Endothelial Cell Autophagy Through Upregulation with Rab4","volume":"35","author":"Yao","year":"2016","journal-title":"DNA Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e1827","DOI":"10.1038\/cddis.2015.193","article-title":"Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression","volume":"6","author":"Liu","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"E8675","DOI":"10.1073\/pnas.1702223114","article-title":"Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow","volume":"114","author":"Vion","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"C383","DOI":"10.1152\/ajpcell.00164.2011","article-title":"Role of autophagy in angiogenesis in aortic endothelial cells","volume":"302","author":"Du","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1042\/BJ20121344","article-title":"PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress","volume":"451","author":"Salabei","year":"2013","journal-title":"Biochem. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"H557","DOI":"10.1152\/ajpheart.00659.2014","article-title":"Defective autophagy in vascular smooth muscle cells alters contractility and Ca2+ homeostasis in mice","volume":"308","author":"Michiels","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1038\/ki.2012.482","article-title":"Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release","volume":"83","author":"Dai","year":"2013","journal-title":"Kidney Int."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.ijcard.2012.12.045","article-title":"Regulation of autophagy and apoptosis in response to ox-LDL in vascular smooth muscle cells, and the modulatory effects of the microRNA hsa-let-7 g","volume":"168","author":"Ding","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13531","DOI":"10.1073\/pnas.1735526100","article-title":"Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading","volume":"100","author":"Rong","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1194\/jlr.M005702","article-title":"Autophagy plays a protective role in free cholesterol overload-induced death of smooth muscle cells","volume":"51","author":"Xu","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.cmet.2011.03.023","article-title":"Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase","volume":"13","author":"Ouimet","year":"2011","journal-title":"Cell Metab."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1161\/ATVBAHA.111.240705","article-title":"Regulation of lipid droplet cholesterol efflux from macrophage foam cells","volume":"32","author":"Ouimet","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/35025203","article-title":"Atherosclerosis","volume":"407","author":"Lusis","year":"2000","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1111\/bph.13052","article-title":"Autophagy: An emerging therapeutic target in vascular diseases","volume":"172","author":"Vindis","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1161\/CIRCRESAHA.116.303804","article-title":"Autophagy in vascular disease","volume":"116","author":"Grootaert","year":"2015","journal-title":"Circ. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/cdd.2010.149","article-title":"HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs","volume":"18","author":"Muller","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"541","DOI":"10.4161\/auto.7.5.15003","article-title":"Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: Prevention by HDLs","volume":"7","author":"Muller","year":"2011","journal-title":"Autophagy"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"28821","DOI":"10.18632\/oncotarget.8936","article-title":"Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids","volume":"7","author":"Swiader","year":"2016","journal-title":"Oncotarget"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1080\/15548627.2015.1096485","article-title":"Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis","volume":"11","author":"Grootaert","year":"2015","journal-title":"Autophagy"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1080\/15548627.2018.1501132","article-title":"Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis","volume":"14","author":"Osonoi","year":"2018","journal-title":"Autophagy"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.cmet.2012.02.011","article-title":"Autophagy links inflammasomes to atherosclerotic progression","volume":"15","author":"Razani","year":"2012","journal-title":"Cell Metab."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cmet.2012.01.022","article-title":"Macrophage autophagy plays a protective role in advanced atherosclerosis","volume":"15","author":"Liao","year":"2012","journal-title":"Cell Metab."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"ra2","DOI":"10.1126\/scisignal.aad5614","article-title":"Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis","volume":"9","author":"Sergin","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/JCI78652","article-title":"Autophagy: A druggable process that is deregulated in aging and human disease","volume":"125","author":"Kroemer","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1093\/gerona\/gls085","article-title":"Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats","volume":"67","author":"Sequea","year":"2012","journal-title":"J. Gerontol. Biol. Sci. Med. Sci."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.molmet.2015.09.006","article-title":"High intensity interval training improves liver and adipose tissue insulin sensitivity","volume":"4","author":"Marcinko","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"46","DOI":"10.4161\/15548627.2014.984271","article-title":"Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway","volume":"11","author":"Song","year":"2015","journal-title":"Autophagy"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"e472","DOI":"10.1038\/cddis.2012.202","article-title":"Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet","volume":"4","author":"Leontieva","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12967-015-0450-z","article-title":"Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK\/mTOR signaling pathway","volume":"13","author":"Fan","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/j.bcp.2012.07.018","article-title":"Berberine: New perspectives for old remedies","volume":"84","author":"Tillhon","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"eaan2788","DOI":"10.1126\/science.aan2788","article-title":"Spermidine in health and disease","volume":"359","author":"Madeo","year":"2018","journal-title":"Science"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ejphar.2014.01.073","article-title":"Exogenous administration of spermine improves glucose utilization and decreases bodyweight in mice","volume":"729","author":"Sadasivan","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1038\/s41467-018-03939-w","article-title":"A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes","volume":"9","author":"Lim","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1080\/15548627.2018.1493044","article-title":"TFEB-dependent induction of thermogenesis by the hepatocyte SLC2A inhibitor trehalose","volume":"14","author":"Zhang","year":"2018","journal-title":"Autophagy"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.freeradbiomed.2016.09.009","article-title":"Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis","volume":"99","author":"Lee","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.1038\/ncomms5834","article-title":"Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers","volume":"5","author":"Park","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jacc.2006.09.047","article-title":"Selective clearance of macrophages in atherosclerotic plaques by autophagy","volume":"49","author":"Verheye","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.1215135","article-title":"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity","volume":"335","author":"Lamming","year":"2012","journal-title":"Science"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/7\/10\/149\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:22:10Z","timestamp":1760196130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/7\/10\/149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,24]]},"references-count":139,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["cells7100149"],"URL":"https:\/\/doi.org\/10.3390\/cells7100149","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,24]]}}}