Obesity poses a severe threat to human health, including the increased prevalence of hypertension, insulin resistance, diabetes mellitus, cancer, inflammation, sleep apnoea and other chronic diseases. Current therapies focus mainly on suppressing caloric intake, but the efficacy of this approach remains poor. A better understanding of the pathophysiology of obesity will be essential for the management of obesity and its complications. Knowledge gained over the past three decades regarding the aetiological mechanisms underpinning obesity has provided a framework that emphasizes energy imbalance and neurohormonal dysregulation, which are tightly regulated by autophagy. Accordingly, there is an emerging interest in the role of autophagy, a conserved homeostatic process for cellular quality control through the disposal and recycling of cellular components, in the maintenance of cellular homeostasis and organ function by selectively ridding cells of potentially toxic proteins, lipids and organelles. Indeed, defects in autophagy homeostasis are implicated in metabolic disorders, including obesity, insulin resistance, diabetes mellitus and atherosclerosis. In this Review, the alterations in autophagy that occur in response to nutrient stress, and how these changes alter the course of obesogenesis and obesity-related complications, are discussed. The potential of pharmacological modulation of autophagy for the management of obesity is also addressed.
Autophagy regulates cellular energy as well as amino acid, glucose and lipid metabolism; conversely, levels of ATP, amino acids, fatty acids and glucose govern autophagy regulation.
Autophagy might be either enhanced or suppressed in obesity owing to dyslipidaemia or overnutrition, respectively, and dysregulation of autophagy promotes the onset and development of metabolic disorders.
Dysregulation of autophagy exhibits tissue specificity and chronological biphasic changes throughout the course of overnutrition and, consequently, obesogenesis.
Loss of autophagy homeostasis in adipose tissue (for example, diminished adipocyte autophagy despite elevated expression of autophagy genes) has unfavourable effects on local and/or global metabolism that promote metabolic disorders.
Lifestyle modification (such as exercise and dietary restriction) and pharmacological modulation of autophagy have been proved beneficial for the prevention and treatment of obesity and its complications.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bastien, M., Poirier, P., Lemieux, I. & Despres, J. P. Overview of epidemiology and contribution of obesity to cardiovascular disease. Prog. Cardiovasc. Dis. 56, 369–381 (2014).
Maiano, C., Hue, O., Morin, A. J. & Moullec, G. Prevalence of overweight and obesity among children and adolescents with intellectual disabilities: a systematic review and meta-analysis. Obes. Rev. 17, 599–611 (2016).
Zylke, J. W. & Bauchner, H. The unrelenting challenge of obesity. JAMA 315, 2277–2278 (2016).
Flegal, K. M., Kruszon-Moran, D., Carroll, M. D., Fryar, C. D. & Ogden, C. L. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315, 2284–2291 (2016).
Ogden, C. L. et al. Trends in obesity prevalence among children and adolescents in the United States, 1988–1994 through 2013–2014. JAMA 315, 2292–2299 (2016).
Curfman, G. D., Morrissey, S. & Drazen, J. M. Sibutramine — another flawed diet pill. N. Engl. J. Med. 363, 972–974 (2010).
Vetter, M. L., Faulconbridge, L. F., Webb, V. L. & Wadden, T. A. Behavioral and pharmacologic therapies for obesity. Nat. Rev. Endocrinol. 6, 578–588 (2010).
Ochner, C. N., Barrios, D. M., Lee, C. D. & Pi-Sunyer, F. X. Biological mechanisms that promote weight regain following weight loss in obese humans. Physiol. Behav. 120, 106–113 (2013).
Afshin, A. et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).
Jacome-Sosa, M. M. & Parks, E. J. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr. Opin. Lipidol. 25, 213–220 (2014).
Hubler, M. J. & Kennedy, A. J. Role of lipids in the metabolism and activation of immune cells. J. Nutr. Biochem. 34, 1–7 (2016).
Ortega, F. B., Lavie, C. J. & Blair, S. N. Obesity and cardiovascular disease. Circ. Res. 118, 1752–1770 (2016).
Zhang, Y. & Ren, J. Epigenetics and obesity cardiomyopathy: from pathophysiology to prevention and management. Pharmacol. Ther. 161, 52–66 (2016).
Zhang, Y. P., Zhang, Y. Y. & Duan, D. D. From genome-wide association study to phenome-wide association study: new paradigms in obesity research. Prog. Mol. Biol. Transl Sci. 140, 185–231 (2016).
Levine, B., Packer, M. & Codogno, P. Development of autophagy inducers in clinical medicine. J. Clin. Invest. 125, 14–24 (2015).
Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).
Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 1845–1846 (2013).
Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
Ignacio-Souza, L. M. et al. Defective regulation of the ubiquitin/proteasome system in the hypothalamus of obese male mice. Endocrinology 155, 2831–2844 (2014).
Jaishy, B. et al. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. J. Lipid Res. 56, 546–561 (2015).
Juarez-Rojas, J. G., Reyes-Soffer, G., Conlon, D. & Ginsberg, H. N. Autophagy and cardiometabolic risk factors. Rev. Endocr. Metabol. Disord. 15, 307–315 (2014).
Meng, Q. & Cai, D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkB kinase β (IKKβ)/NF-kB pathway. J. Biol. Chem. 286, 32324–32332 (2011).
Kovsan, J. et al. Altered autophagy in human adipose tissues in obesity. J. Clin. Endocrinol. Metab. 96, E268–277 (2011).
Jansen, H. J. et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153, 5866–5874 (2012).
Kosacka, J. et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol. Cell. Endocrinol. 409, 21–32 (2015).
Mu, Y. et al. Diet-induced obesity impairs spermatogenesis: a potential role for autophagy. Sci. Rep. 7, 43475 (2017).
Yamahara, K. et al. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J. Am. Soc. Nephrol. 24, 1769–1781 (2013).
Soussi, H., Clement, K. & Dugail, I. Adipose tissue autophagy status in obesity: Expression and flux — two faces of the picture. Autophagy 12, 588–589 (2016).
Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1–222 (2016).
Kim, K. H. & Lee, M. S. Autophagy — a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10, 322–337 (2014).
Lee, H. Y. et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy 12, 1390–1403 (2016).
Sinha, R. A., Singh, B. K. & Yen, P. M. Reciprocal crosstalk between autophagic and endocrine signaling in metabolic homeostasis. Endocr. Rev. 38, 69–102 (2017).
Cheng, Y., Ren, X., Hait, W. N. & Yang, J. M. Therapeutic targeting of autophagy in disease: biology and pharmacology. Pharmacol. Rev. 65, 1162–1197 (2013).
Harding, T. M., Morano, K. A., Scott, S. V. & Klionsky, D. J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602 (1995).
Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).
Liu, Y. & Levine, B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 22, 367–376 (2015).
Madrigal-Matute, J. & Cuervo, A. M. Regulation of liver metabolism by autophagy. Gastroenterology 150, 328–339 (2016).
Evans, T. D., Sergin, I., Zhang, X. & Razani, B. Target acquired: selective autophagy in cardiometabolic disease. Sci. Signal. 10, eaag2298 (2017).
Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018).
Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).
Lavallard, V. J., Meijer, A. J., Codogno, P. & Gual, P. Autophagy, signaling and obesity. Pharmacol. Res. 66, 513–525 (2012).
Botti-Millet, J., Nascimbeni, A. C., Dupont, N., Morel, E. & Codogno, P. Fine-tuning autophagy: from transcriptional to posttranslational regulation. Am. J. Physiol. Cell Physiol. 311, C351–C362 (2016).
Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).
Broer, S. & Broer, A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem. J. 474, 1935–1963 (2017).
Sciarretta, S. et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125, 1134–1146 (2012).
Han, J. M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012).
Yuan, W. et al. General control nonderepressible 2 (GCN2) kinase inhibits target of rapamycin complex 1 in response to amino acid starvation in Saccharomyces cerevisiae. J. Biol. Chem. 292, 2660–2669 (2017).
Shimobayashi, M. & Hall, M. N. Multiple amino acid sensing inputs to mTORC1. Cell Res. 26, 7–20 (2016).
Meijer, A. J., Lorin, S., Blommaart, E. F. & Codogno, P. Regulation of autophagy by amino acids and MTOR-dependent signal transduction. Amino Acids 47, 2037–2063 (2015).
Zhang, F. et al. Branched chain amino acids cause liver injury in obese/diabetic mice by promoting adipocyte lipolysis and inhibiting hepatic autophagy. EBioMedicine 13, 157–167 (2016).
Zhou, J. et al. Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging. Aging 9, 583–599 (2017).
Tan, H. W. S., Sim, A. Y. L. & Long, Y. C. Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation. Nat. Commun. 8, 338 (2017).
James, H. A., O’Neill, B. T. & Nair, K. S. Insulin regulation of proteostasis and clinical implications. Cell. Metab. 26, 310–323 (2017).
Ng, F. & Tang, B. L. Sirtuins’ modulation of autophagy. J. Cell. Physiol. 228, 2262–2270 (2013).
Wang, K. Molecular mechanism of hepatic steatosis: pathophysiological role of autophagy. Expert Rev. Mol. Med. 18, e14 (2016).
Koga, H., Kaushik, S. & Cuervo, A. M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052–3065 (2010).
Engin, A. Non-alcoholic fatty liver disease. Adv. Exp. Med. Biol. 960, 443–467 (2017).
Komiya, K. et al. Free fatty acids stimulate autophagy in pancreatic beta-cells via JNK pathway. Biochem. Biophys. Res. Commun. 401, 561–567 (2010).
Tan, S. H. et al. Induction of autophagy by palmitic acid via protein kinase C-mediated signaling pathway independent of mTOR (mammalian target of rapamycin). J. Biol. Chem. 287, 14364–14376 (2012).
Nguyen, T. B. & Olzmann, J. A. Lipid droplets and lipotoxicity during autophagy. Autophagy 13, 2002–2003 (2017).
Cabandugama, P. K., Gardner, M. J. & Sowers, J. R. The renin angiotensin aldosterone system in obesity and hypertension: roles in the cardiorenal metabolic syndrome. Med. Clin. North Am. 101, 129–137 (2017).
Oga, E. A. & Eseyin, O. R. The obesity paradox and heart failure: a systematic review of a decade of evidence. J. Obes. 2016, 9040248 (2016).
He, C. et al. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154, 1085–1099 (2013).
Liu, Y. et al. Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin resistance. Sci. Rep. 6, 20453 (2016).
Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).
Yasuda-Yamahara, M. et al. Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure. Biochem. Biophys. Res. Commun. 465, 249–255 (2015).
Halban, P. A., Mutkoski, R., Dodson, G. & Orci, L. Resistance of the insulin crystal to lysosomal proteases: implications for pancreatic B cell crinophagy. Diabetologia 30, 348–353 (1987).
Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell. Metab. 11, 467–478 (2010).
Singh, R. et al. Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest. 119, 3329–3339 (2009).
Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc. Natl Acad. Sci. USA 106, 19860–19865 (2009).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Shibata, M. et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem. Biophys. Res. Commun. 382, 419–423 (2009).
Quan, W. et al. Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153, 1817–1826 (2012).
Lim, Y. M. et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat. Commun. 5, 4934 (2014).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Lapierre, L. R., Kumsta, C., Sandri, M., Ballabio, A. & Hansen, M. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11, 867–880 (2015).
Mader, B. J. et al. Rotenone inhibits autophagic flux prior to inducing cell death. ACS Chem. Neurosci. 3, (1063–1072 (2012).
Shin, H. J. et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534, 553–557 (2016).
Wang, S. et al. ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1 and PGC-1α deacetylation. Int. J. Obes. https://doi.org/10.1038/s41366-018-0030-4 (2018).
Mattson, M. P., Longo, V. D. & Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 39, 46–58 (2017).
Krishan, P., Singh, G. & Bedi, O. Carbohydrate restriction ameliorates nephropathy by reducing oxidative stress and upregulating HIF-1alpha levels in type-1 diabetic rats. J. Diabetes Metab. Disord. 16, 47 (2017).
Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 29, 2570–2581 (2009).
Alexander, A., Kim, J. & Walker, C. L. ATM engages the TSC2/mTORC1 signaling node to regulate autophagy. Autophagy 6, 672–673 (2010).
Scherz-Shouval, R. et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749–1760 (2007).
Madeo, F., Pietrocola, F., Eisenberg, T. & Kroemer, G. Caloric restriction mimetics: towards a molecular definition. Nat. Rev. Drug Discov. 13, 727–740 (2014).
Tao, J. et al. Downregulation of Nrf2 promotes autophagy-dependent osteoblastic differentiation of adipose-derived mesenchymal stem cells. Exp. Cell Res. 349, 221–229 (2016).
Maixner, N. et al. Transcriptional dysregulation of adipose tissue autophagy in obesity. Physiology 31, 270–282 (2016).
Jia, G., Aroor, A. R. & Sowers, J. R. The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall. Cardiovasc. Res. 113, 1055–1063 (2017).
Shiau, M. Y. et al. Role of PARL-PINK1-Parkin pathway in adipocyte differentiation. Metabolism 72, 1–17 (2017).
Mandviwala, T., Khalid, U. & Deswal, A. Obesity and cardiovascular disease: a risk factor or a risk marker? Curr. Atheroscler. Rep. 18, 21 (2016).
Haim, Y. et al. Elevated autophagy gene expression in adipose tissue of obese humans: a potential non-cell-cycle-dependent function of E2F1. Autophagy 11, 2074–2088 (2015).
Soussi, H. et al. DAPK2 downregulation associates with attenuated adipocyte autophagic clearance in human obesity. Diabetes 64, 3452–3463 (2015).
Haim, Y. et al. ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype. Mol. Metab. 6, 725–736 (2017).
Slutsky, N. et al. Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity. Int. J. Obes. 40, 912–920 (2016).
Mizunoe, Y. et al. Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice. Autophagy 13, 642–653 (2017).
Liu, K. et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 11, 271–284 (2015).
Xu, X. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell. Metab. 18, 816–830 (2013).
Kang, Y. H. et al. Impaired macrophage autophagy induces systemic insulin resistance in obesity. Oncotarget 7, 35577–35591 (2016).
Bechor, S. et al. Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux. Biochim. Biophys. Acta 1862, 1001–1012 (2017).
Grijalva, A., Xu, X. & Ferrante, A. W. Jr. Autophagy is dispensable for macrophage-mediated lipid homeostasis in adipose tissue. Diabetes 65, 967–980 (2016).
Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell. Metabolism 13, 655–667 (2011).
Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692 (2015).
Ye, J. Mechanisms of insulin resistance in obesity. Front. Med. 7, 14–24 (2013).
Goginashvili, A. et al. Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells. Science 347, 878–882 (2015).
Yamaguchi, H. et al. Golgi membrane-associated degradation pathway in yeast and mammals. EMBO J. 35, 1991–2007 (2016).
Jia, G., DeMarco, V. G. & Sowers, J. R. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat. Rev. Endocrinol. 12, 144–153 (2016).
Li, R. et al. 1,25(OH)2 D3 attenuates hepatic steatosis by inducing autophagy in mice. Obesity 25, 561–571 (2017).
Song, Y. M. et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 11, 46–59 (2015).
Jia, G., Hill, M. A. & Sowers, J. R. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ. Res. 122, 624–638 (2018).
Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).
Quan, W. et al. Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia 55, 392–403 (2012).
Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell. Metab. 8, 325–332 (2008).
Jung, H. S. et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell. Metab. 8, 318–324 (2008).
Chang, H. H. et al. Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. PLoS ONE 12, e0184455 (2017).
Liu, H. et al. Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway. Autophagy 13, 1952–1968 (2017).
Aoyagi, K. et al. VAMP7 regulates autophagy to maintain mitochondrial homeostasis and to control insulin secretion in pancreatic beta-cells. Diabetes 65, 1648–1659 (2016).
Abe, H. et al. Exendin-4 improves beta-cell function in autophagy-deficient beta-cells. Endocrinology 154, 4512–4524 (2013).
Chu, K. Y., O’Reilly, L., Ramm, G. & Biden, T. J. High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice. Diabetologia 58, 2074–2078 (2015).
Sun, Q. et al. Factors that affect pancreatic islet cell autophagy in adult rats: evaluation of a calorie-restricted diet and a high-fat diet. PLoS ONE 11, e0151104 (2016).
Marsh, B. J. et al. Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Mol. Endocrinol. 21, 2255–2269 (2007).
Fujitani, Y., Ueno, T. & Watada, H. Autophagy in health and disease. 4. The role of pancreatic beta-cell autophagy in health and diabetes. American journal of physiology. Cell Physiol. 299, C1–C6 (2010).
Inoki, K., Kim, J. & Guan, K. L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012).
Fujitani, Y., Kawamori, R. & Watada, H. The role of autophagy in pancreatic beta-cell and diabetes. Autophagy 5, 280–282 (2009).
Houstis, N., Rosen, E. D. & Lander, E. S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 (2006).
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G. I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).
Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, (1640–1645 (2009).
Despres, J. P. Abdominal obesity and cardiovascular disease: is inflammation the missing link? Can. J. Cardiol. 28, 642–652 (2012).
van Greevenbroek, M. M., Schalkwijk, C. G. & Stehouwer, C. D. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth. J. Med. 71, 174–187 (2013).
Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).
Joven, J., Guirro, M., Marine-Casado, R., Rodriguez-Gallego, E. & Menendez, J. A. Autophagy is an inflammation-related defensive mechanism against disease. Adv. Exp. Med. Biol. 824, 43–59 (2014).
Cordero, M. D., Williams, M. R. & Ryffel, B. AMP-activated protein kinase regulation of the NLRP3 inflammasome during aging. Trends Endocrinol. Metab. 29, 8–17 (2018).
Cosin-Roger, J. et al. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat. Commun. 8, 98 (2017).
Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell 166, 288–298 (2016).
Lapaquette, P., Guzzo, J., Bretillon, L. & Bringer, M. A. Cellular and molecular connections between autophagy and inflammation. Mediators Inflamm. 2015, 398483 (2015).
Jounai, N. et al. NLRP4 negatively regulates autophagic processes through an association with beclin1. J. Immunol. 186, 1646–1655 (2011).
Cao, L. et al. CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity. J. Mol. Cell. Cardiol. 92, 185–195 (2016).
An, M. et al. ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism. Cardiovasc. Res. 113, 1137–1147 (2017).
Hu, N. & Zhang, Y. TLR4 knockout attenuated high fat diet-induced cardiac dysfunction via NF-kappaB/JNK-dependent activation of autophagy. Biochim. Biophys. Acta 1863, 2001–2011 (2017).
Xu, X., Hua, Y., Nair, S., Zhang, Y. & Ren, J. Akt2 knockout preserves cardiac function in high-fat diet-induced obesity by rescuing cardiac autophagosome maturation. J. Mol. Cell Biol. 5, 61–63 (2013).
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001).
Zhang, Y., Xu, X. & Ren, J. MTOR overactivation and interrupted autophagy flux in obese hearts: a dicey assembly? Autophagy 9, 939–941 (2013).
He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).
Li, Z. L. et al. Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis. Arterioscler. Thromb. Vasc. Biol. 32, 1132–1141 (2012).
Li, Z. L. et al. Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function. Am. J. Physiol.Heart Circ. Physiol. 306, H1087–H1101 (2014).
Xu, X. & Ren, J. Macrophage migration inhibitory factor (MIF) knockout preserves cardiac homeostasis through alleviating Akt-mediated myocardial autophagy suppression in high-fat diet-induced obesity. Int. J. Obes. 39, 387–396 (2015).
Kandadi, M. R. et al. Deletion of protein tyrosine phosphatase 1B rescues against myocardial anomalies in high fat diet-induced obesity: role of AMPK-dependent autophagy. Biochim. Biophys. Acta 1852, 299–309 (2015).
Liang, L. et al. Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKbeta-AMPK-dependent regulation of autophagy. Biochim. Biophys. Acta 1852, 343–352 (2015).
Guo, R., Zhang, Y., Turdi, S. & Ren, J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim. Biophys. Acta 1832, 1136–1148 (2013).
Lai, C. H. et al. Multi-strain probiotics inhibit cardiac myopathies and autophagy to prevent heart injury in high-fat diet-fed rats. Int. J. Med. Sci. 13, 277–285 (2016).
Yan, Z. et al. Exercise leads to unfavourable cardiac remodelling and enhanced metabolic homeostasis in obese mice with cardiac and skeletal muscle autophagy deficiency. Sci. Rep. 7, 7894 (2017).
Dong, Q. et al. Tetrahydroxystilbene glycoside improves microvascular endothelial dysfunction and ameliorates obesity-associated hypertension in obese ZDF rats via inhibition of endothelial autophagy. Cell. Physiol. Biochem. 43, 293–307 (2017).
Cheng, C. I. et al. Free fatty acids induce autophagy and LOX-1 upregulation in cultured aortic vascular smooth muscle cells. J. Cell. Biochem. 118, 1249–1261 (2017).
Messerli, F. H., Rimoldi, S. F. & Bangalore, S. The transition from hypertension to heart failure: contemporary update. JACC Heart Fail. 5, 543–551 (2017).
Pfeifer, U., Föhr, J., Wilhelm, W. & Dämmrich, J. Short-term inhibition of cardiac cellular autophagy by isoproterenol. J. Mol. Cell. Cardiol. 19, 1179–1184 (1987).
Shirakabe, A. et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133, 1249–1263 (2016).
De Meyer, G. R. et al. Autophagy in vascular disease. Circ. Res. 116, 468–479 (2015).
Nielsen, J. Systems biology of metabolism: a driver for developing personalized and precision medicine. Cell. Metab. 25, 572–579 (2017).
Yu, W. et al. Sirt3 deficiency exacerbates diabetic cardiac dysfunction: Role of Foxo3A-Parkin-mediated mitophagy. Biochim. Biophys. Acta 1863, 1973–1983 (2017).
Negri, T. et al. Chromosome band 17q21 in breast cancer: significant association between beclin 1 loss and HER2/NEU amplification. Genes Chromosomes Cancer 49, 901–909 (2010).
Li, S. et al. SIRT3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity. Hepatology 66, 936–952 (2017).
Shen, C. et al. Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1-dependent autophagy induction. Nutr. Res. 40, 40–47 (2017).
Ueno, T. & Komatsu, M. Autophagy in the liver: functions in health and disease. Nat. Rev. Gastroenterol. Hepatol. 14, 170–184 (2017).
Aijala, M. et al. Long-term fructose feeding changes the expression of leptin receptors and autophagy genes in the adipose tissue and liver of male rats: a possible link to elevated triglycerides. Genes Nutr. 8, 623–635 (2013).
He, Q., Sha, S., Sun, L., Zhang, J. & Dong, M. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem. Biophys. Res. Commun. 476, 196–203 (2016).
Chang, E. et al. Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J. Gastroenterol. 21, 7754–7763 (2015).
Guo, R., Nair, S., Zhang, Y. & Ren, J. Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis. Int. J. Obes. 41, 1403–1412 (2017).
Kim, S. H. et al. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy 13, 1767–1781 (2017).
Liu, J. & Debnath, J. The evolving, multifaceted roles of autophagy in cancer. Adv. Cancer Res. 130, 1–53 (2016).
Tanaka, S. et al. Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology 64, 1994–2014 (2016).
Kaushik, S. & Cuervo, A. M. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat. Cell Biol. 17, 759–770 (2015).
Martinez-Vicente, M. Neuronal Mitophagy in neurodegenerative diseases. Front. Mol. Neurosci. 10, 64 (2017).
Chen, Y., Xu, C., Yan, T., Yu, C. & Li, Y. Omega-3 fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease. Nutrition 31, 1423–1429.e2 (2015).
Hsu, H. C. et al. Time-dependent cellular response in the liver and heart in a dietary-induced obese mouse model: the potential role of ER stress and autophagy. Eur. J. Nutr. 55, 2031–2043 (2016).
Mao, Y., Yu, F., Wang, J., Guo, C. & Fan, X. Autophagy: a new target for nonalcoholic fatty liver disease therapy. Hepat. Med. 8, 27–37 (2016).
Lin, C. W. et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58, 993–999 (2013).
Guo, R., Xu, X., Babcock, S. A., Zhang, Y. & Ren, J. Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy. J. Hepatol. 62, 647–656 (2015).
Bani Mohammad, M. & Majdi Seghinsara, A. Polycystic ovary syndrome (PCOS), diagnostic criteria, and AMH. Asian Pac. J. Cancer Prev. 18, 17–21 (2017).
Sumarac-Dumanovic, M. et al. Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome. Mol. Cell. Endocrinol. 440, 116–124 (2017).
Su, Y. et al. High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process. Endocr. J. 64, 613–621 (2017).
Gao, L. et al. Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome. Endocrine 52, 363–373 (2016).
Zhang, Y. et al. Metformin ameliorates uterine defects in a rat model of polycystic ovary syndrome. EBioMedicine 18, 157–170 (2017).
Dong, M., Zheng, Q., Ford, S. P., Nathanielsz, P. W. & Ren, J. Maternal obesity, lipotoxicity and cardiovascular diseases in offspring. J. Mol. Cell. Cardiol. 55, 111–116 (2013).
Muralimanoharan, S., Gao, X., Weintraub, S., Myatt, L. & Maloyan, A. Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model. Autophagy 12, 752–769 (2016).
Reginato, A. et al. Autophagy proteins are modulated in the liver and hypothalamus of the offspring of mice with diet-induced obesity. J. Nutr. Biochem. 34, 30–41 (2016).
Boudoures, A. L. et al. Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. Dev. Biol. 426, 126–138 (2017).
Navarro, E., Funtikova, A. N., Fito, M. & Schroder, H. Prenatal nutrition and the risk of adult obesity: long-term effects of nutrition on epigenetic mechanisms regulating gene expression. J. Nutr. Biochem. 39, 1–14 (2017).
Zhu, S., Eclarinal, J., Baker, M. S., Li, G. & Waterland, R. A. Developmental programming of energy balance regulation: is physical activity more ‘programmable’ than food intake? Proc. Nutr. Soc. 75, 73–77 (2016).
Wong, A. K. et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur. J. Heart Fail. 14, 1303–1310 (2012).
Jia, G., Jia, Y. & Sowers, J. R. Contribution of maladaptive adipose tissue expansion to development of cardiovascular disease. Compr. Physiol. 7, 253–262 (2016).
Jiang, Y. et al. Metformin plays a dual role in MIN6 pancreatic beta cell function through AMPK-dependent autophagy. Int. J. Biol. Sci. 10, 268–277 (2014).
Hsiao, P. J. et al. Pioglitazone enhances cytosolic lipolysis, beta-oxidation and autophagy to ameliorate hepatic steatosis. Sci. Rep. 7, 9030 (2017).
Liu, Y. et al. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes 64, 36–48 (2015).
Hussain, Z. & Khan, J. A. Food intake regulation by leptin: mechanisms mediating gluconeogenesis and energy expenditure. Asian Pac. J. Trop. Med. 10, 940–944 (2017).
Sun, F. et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J. Diabetes Res. 2015, 157201 (2015).
Tomlinson, B., Hu, M., Zhang, Y., Chan, P. & Liu, Z. M. Investigational glucagon-like peptide-1 agonists for the treatment of obesity. Expert Opin. Invest. Drugs 25, 1167–1179 (2016).
Sharma, S., Mells, J. E., Fu, P. P., Saxena, N. K. & Anania, F. A. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 6, e25269 (2011).
Venkatanarayan, A. et al. IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo. Nature 517, 626–630 (2015).
Alcocer-Gomez, E. et al. Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in major depressive disorder. Pharmacol. Res. 121, 114–121 (2017).
Morissette, G., Lodge, R., Bouthillier, J. & Marceau, F. Receptor-independent, vacuolar ATPase-mediated cellular uptake of histamine receptor-1 ligands: possible origin of pharmacological distortions and side effects. Toxicol. Appl. Pharmacol. 229, 320–331 (2008).
Hiebel, C., Kromm, T., Stark, M. & Behl, C. Cannabinoid receptor 1 modulates the autophagic flux independent of mTOR- and BECLIN1-complex. J. Neurochem. 131, 484–497 (2014).
Choi, S. S. et al. PPARgamma antagonist gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes 65, 829–839 (2016).
Paech, F., Bouitbir, J. & Krahenbuhl, S. Hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front. Pharmacol. 8, 367 (2017).
Courtney, H., Nayar, R., Rajeswaran, C. & Jandhyala, R. Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists. Diabetes Metab. Syndr. Obes. 10, 79–87 (2017).
Xu, L. et al. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine 20, 137–149 (2017).
Guo, H. et al. Glucagon-like peptide-1 analog prevents obesity-related glomerulopathy by inhibiting excessive autophagy in podocytes. Am. J. Physiol. Renal Physiol. 314, F181–F189 (2018).
Parray, H. A. & Yun, J. W. Combined inhibition of autophagy protein 5 and galectin-1 by thiodigalactoside reduces diet-induced obesity through induction of white fat browning. IUBMB Life 69, 510–521 (2017).
Wang, S. & Peng, D. Regulation of adipocyte autophagy — the potential anti-obesity mechanism of high density lipoprotein and ApolipoproteinA-I. Lipids Health Dis. 11, 131 (2012).
Quatraro, A. et al. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug? Ann. Intern. Med. 112, 678–681 (1990).
Gerstein, H. C., Thorpe, K. E., Taylor, D. W. & Haynes, R. B. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas — a randomized trial. Diabetes Res. Clin. Pract. 55, 209–219 (2002).
Wasko, M. C. et al. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial. Diabetologia 58, 2336–2343 (2015).
Alrushud, A. S., Rushton, A. B., Kanavaki, A. M. & Greig, C. A. Effect of physical activity and dietary restriction interventions on weight loss and the musculoskeletal function of overweight and obese older adults with knee osteoarthritis: a systematic review and mixed method data synthesis. BMJ Open 7, e014537 (2017).
Webb, V. L. & Wadden, T. A. Intensive lifestyle intervention for obesity: principles, practices, and results. Gastroenterology 152, 1752–1764 (2017).
Han, X. et al. Influence of long-term caloric restriction on myocardial and cardiomyocyte contractile function and autophagy in mice. J. Nutr. Biochem. 23, 1592–1599 (2012).
Kitzman, D. W. et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 315, 36–46 (2016).
Ludwig, D. S. Lifespan weighed down by diet. JAMA 315, 2269–2270 (2016).
Halling, J. F. & Pilegaard, H. Autophagy-dependent beneficial effects of exercise. Cold Spring Harb. Perspect. Med. 7, a029777 (2017).
Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell. Metab. 26, 547–557.e8 (2017).
Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell. Metab. 26, 539–546 e5 (2017).
Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).
Ma, D. et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol. Endocrinol. 27, 1643–1654 (2013).
Jaber, N. et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. USA 109, 2003–2008 (2012).
Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).
Shigihara, N. et al. Human IAPP-induced pancreatic beta cell toxicity and its regulation by autophagy. J. Clin. Invest. 124, 3634–3644 (2014).
Fernandez, A. F. et al. Autophagy couteracts weight gain, lipotoxicity and pancreatic beta-cell death upon hypercaloric pro-diabetic regimens. Cell Death Dis. 8, e2970 (2017).
Liu, L., Liu, J. & Yu, X. Dipeptidyl peptidase-4 inhibitor MK-626 restores insulin secretion through enhancing autophagy in high fat diet-induced mice. Biochem. Biophys. Res. Commun. 470, 516–520 (2016).
Gao, X., Yan, D., Zhao, Y., Tao, H. & Zhou, Y. Moderate calorie restriction to achieve normal weight reverses beta-cell dysfunction in diet-induced obese mice: involvement of autophagy. Nutr. Metab. 12, 34 (2015).
Soeda, J. et al. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. J. Physiol. Biochem. 72, 281–291 (2016).
Lopez-Vicario, C. et al. Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides. Proc. Natl Acad. Sci. USA 112, 536–541 (2015).
He, B., Liu, L., Yu, C., Wang, Y. & Han, P. Roux-en-Y gastric bypass reduces lipid overaccumulation in liver by upregulating hepatic autophagy in obese diabetic rats. Obes. Surg. 25, 109–118 (2015).
Rodriguez-Navarro, J. A. et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 109, E705–E714 (2012).
Liu, H. Y. et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J. Biol. Chem. 284, 31484–31492 (2009).
Inami, Y. et al. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression. Biochem. Biophys. Res. Commun. 412, 618–625 (2011).
Parafati, M. et al. Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. J. Nutr. Biochem. 26, 938–948 (2015).
Xiao, J. et al. Lycium barbarum polysaccharides therapeutically improve hepatic functions in non-alcoholic steatohepatitis rats and cellular steatosis model. Sci. Rep. 4, 5587 (2014).
Yan, H., Gao, Y. & Zhang, Y. Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model of nonalcoholic fatty liver disease. Mol. Med. Rep. 15, 180–186 (2017).
Xu, Q. et al. Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity. Adipocyte https://doi.org/10.1080/21623945.2017.1394537 (2018).
Matsuura, N. et al. Effects of pioglitazone on cardiac and adipose tissue pathology in rats with metabolic syndrome. Int. J. Cardiol. 179, 360–369 (2015).
Mao, Y. et al. Ghrelin attenuated lipotoxicity via autophagy induction and nuclear factor-kappaB inhibition. Cell. Physiol. Biochem. 37, 563–576 (2015).
Uchinaka, A., Yoneda, M., Yamada, Y., Murohara, T. & Nagata, K. Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome. Pharmacol. Res. Perspect. 5, e00331 (2017).
Kwak, H. J. et al. Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism. Cell. Signal. 28, 788–797 (2016).
Bhattacharya, B. et al. Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. Br. J. Pharmacol. 171, 3255–3267 (2014).
Borriello, A. et al. Resveratrol: from basic studies to bedside. Cancer Treat. Res. 159, 167–184 (2014).
Liu, L., Gao, C., Yao, P. & Gong, Z. Quercetin alleviates high-fat diet-induced oxidized low-density lipoprotein accumulation in the liver: implication for autophagy regulation. BioMed Res. Int. 2015, 607531 (2015).
Necela, B. M. et al. The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes. Clin. Transl Med. 6, 5 (2017).
Bursch, W. et al. Cell death and autophagy: cytokines, drugs, and nutritional factors. Toxicology 254, 147–157 (2008).
The authors received support in part from the National Key R&D Program of China (2017YFA0506000), the American Diabetes Association (7-13-BS-142-BR, NSFC 81522004, NSFC81570225, NSFC81521001, R01 HL73101-01 A and R01 HL107910-01) and the US Veterans Affairs Merit System (0018). The authors express their sincere apology to those authors whose important work cannot be included owing to space limitations.
Nature Reviews Endocrinology thanks H. Watada, and the other anonymous reviewers, for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Nonselective autophagy
Involves the random uptake of portions of the cytoplasm (cytosol and organelles) in the vacuole and/or lysosome for degradation and recycling.
- Cargo-specific autophagy
Selective autophagy characterized by a degradation process that is highly regulated by an autophagy receptor, with sequestration cargo specificity for cytoplasmic contents.
Peptide hormones or cytokines secreted by adipose tissues (including leptin, adiponectin and tumour necrosis factor) that have major roles in multiple biological processes such as glucose and fatty acid metabolism, insulin sensitivity and adipocyte differentiation.
- Starvation-induced nascent granule degradation
(SINGD). Refers to the lysosomal degradation of nascent secretory insulin granules when β-cells are subjected to glucose deprivation; this process triggers lysosomal recruitment and activation of mTOR to suppress autophagy.
- Golgi membrane-associated degradation
(GOMED). Characterized by the generation of Golgi membrane-associated structures accompanied by proteolysis and is activated when Golgi-to-plasma-membrane anterograde trafficking is disrupted in autophagy-deficient yeast and mammalian cells.
Apoptosis caused by exposure to an excess of fatty acids.
- Metabolic inflexibility
Occurs with an inability to adapt fuel oxidation to fuel availability and is characterized by nutrient overload and increased substrate competition, resulting in impaired fuel switching and energy dysregulation.
- Ketogenic diets
High-fat, protein-adequate, low-carbohydrate diets that are used primarily to treat difficult-to-control (refractory) epilepsy in children.
About this article
Cite this article
Zhang, Y., Sowers, J.R. & Ren, J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol 14, 356–376 (2018). https://doi.org/10.1038/s41574-018-0009-1
Acta Pharmacologica Sinica (2021)
Mitochondrial protein IF1 is a potential regulator of glucogan-like peptide (GLP-1) secretion function of mouse intestine
Acta Pharmaceutica Sinica B (2021)
A novel palmitic acid hydroxy stearic acid (5‐PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m‐TOR‐ULK1 pathway and regulating autophagy
CNS Neuroscience & Therapeutics (2021)
Molecular Aspects of Medicine (2021)
Deletion of the E3 ubiquitin ligase, Parkin, exacerbates chronic alcohol intake‐induced cardiomyopathy through an Ambra1‐dependent mechanism
British Journal of Pharmacology (2021)