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TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

A Corrigendum to this article was published on 01 August 2013

This article has been updated


The lysosomal–autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a new therapeutic strategy for disorders of lipid metabolism.

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Figure 1: Autoregulation of TFEB during starvation.
Figure 2: The TFEB lipid metabolism network.
Figure 3: TFEB directly regulates Pgc-1α expression during starvation.
Figure 4: Liver fat catabolism in response to starvation is regulated by TFEB.
Figure 5: TFEB regulates lipid catabolism through the autophagic pathway.
Figure 6: Metabolic profile of HDAd-TFEB-overexpressing mice.
Figure 7: TFEB prevents diet-induced obesity and metabolic syndrome.
Figure 8: Conservation of TFEB-mediated autoregulation and of starvation response in C. elegans.

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  • 25 June 2013

    In the version of this Article originally published, in the Methods section, Supplementary Table S8 was incorrectly cited as listing lipid metabolism gene-specific primers under the heading 'RNA extraction, quantitative PCR and statistical analysis'. The list of gene-specific primers has now been uploaded as Supplementary Table S10 and the citation in the Methods has been amended. This has been corrected in the PDF and HTML versions of this Article.


  1. 1

    Bauer, M. et al. Starvation response in mouse liver shows strong correlation with life-span-prolonging processes. Physiol. Genomics 17, 230–244 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Sokolovic, M. et al. The transcriptomic signature of fasting murine liver. BMC Genomics 9, 528 (2008).

    Article  Google Scholar 

  3. 3

    Hakvoort, T. B. et al. Interorgan coordination of the murine adaptive response to fasting. J. Biol. Chem. 286, 16332–16343 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Finn, P. F. & Dice, J. F. Proteolytic and lipolytic responses to starvation. Nutrition 22, 830–844 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span–from yeast to humans. Science 328, 321–326 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Zinke, I., Schutz, C. S., Katzenberger, J. D., Bauer, M. & Pankratz, M. J. Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response. EMBO J. 21, 6162–6173 (2002).

    CAS  Article  Google Scholar 

  7. 7

    Van Gilst, M. R., Hadjivassiliou, H. & Yamamoto, K. R. A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc. Natl Acad. Sci. USA 102, 13496–13501 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Mizushima, N. Autophagy: process and function. Genes Dev. 21, 2861–2873 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Singh, R. & Cuervo, A. M. Autophagy in the cellular energetic balance. Cell Metab. 13, 495–504 (2011).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Palmieri, M. et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20, 3852–3866 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Dennis, G. Jr. et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4, P3 (2003).

    Article  Google Scholar 

  16. 16

    Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  Google Scholar 

  17. 17

    Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Spiegelman, B. M. & Heinrich, R. Biological control through regulated transcriptional coactivators. Cell 119, 157–167 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell Biol. 20, 1868–1876 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  Google Scholar 

  21. 21

    Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet. 14, 95–97 (1996).

    CAS  Article  Google Scholar 

  25. 25

    Lai, C. H., Chou, C. Y., Ch’ang, L. Y., Liu, C. S. & Lin, W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 10, 703–713 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Grove, C. A. et al. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138, 314–327 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Kaeberlein, T. L. et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5, 487–494 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Johnson, T. E., Mitchell, D. H., Kline, S., Kemal, R. & Foy, J. Arresting development arrests ageing in the nematode Caenorhabditis elegans. Mech. Ageing Dev. 28, 23–40 (1984).

    CAS  Article  Google Scholar 

  29. 29

    Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 1095–1108 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

    CAS  Article  Google Scholar 

  31. 31

    Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal 5, ra42 (2012).

    Article  Google Scholar 

  32. 32

    Becskei, A., Seraphin, B. & Serrano, L. Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Siciliano, V. et al. Construction and modelling of an inducible positive feedback loop stably integrated in a mammalian cell-line. PLoS Comput. Biol. 7, e1002074 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Kielbasa, S. M. & Vingron, M. Transcriptional autoregulatory loops are highly conserved in vertebrate evolution. PLoS One 3, e3210 (2008).

    Article  Google Scholar 

  35. 35

    Handschin, C., Rhee, J., Lin, J., Tarr, P. T. & Spiegelman, B. M. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1α expression in muscle. Proc. Natl Acad. Sci. USA 100, 7111–7116 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Tsunemi, T. et al. PGC- 1α rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra197 (2012).

    Article  Google Scholar 

  37. 37

    Bostrom, P. et al. A PGC1- α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    Article  Google Scholar 

  38. 38

    Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Inagaki, T. et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415–425 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Beale, E. G., Clouthier, D. E. & Hammer, R. E. Cell-specific expression of cytosolic phosphoenolpyruvate carboxykinase in transgenic mice. FASEB J. 6, 3330–3337 (1992).

    CAS  Article  Google Scholar 

  41. 41

    Palmer, D. & Ng, P. Improved system for helper-dependent adenoviral vector production. Mol. Ther. 8, 846–852 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Ng, P., Parks, R. J. & Graham, F. L. Preparation of helper-dependent adenoviral vectors. Methods Mol. Med. 69, 371–388 (2002).

    CAS  PubMed  Google Scholar 

  43. 43

    Li, R. et al. Gene therapy targeting LDL cholesterol but not HDL cholesterol induces regression of advanced atherosclerosis in a mouse model of familial hypercholesterolemia. J Genet Syndr. Gene Ther. 2, 106 (2011).

    Article  Google Scholar 

  44. 44

    Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 8, 918–922 (2012).

    Article  Google Scholar 

  45. 45

    Couture, S., Massicotte, D., Lavoie, C., Hillaire-Marcel, C. & Peronnet, F. Oral [(13)C]glucose and endogenous energy substrate oxidation during prolonged treadmill running. J. Appl. Physiol. 92, 1255–1260 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Edgar, R., Domrachev, M. & Lash, A. E. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).

    CAS  Article  Google Scholar 

  47. 47

    Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  Google Scholar 

  48. 48

    Baldi, P. & Long, A. D. A Bayesian framework for the analysis of microarray expression data: regularized t-test and statistical inferences of gene changes. Bioinformatics 17, 509–519 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Klipper-Aurbach, Y. et al. Mathematical formulae for the prediction of the residual β cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus. Med. Hypotheses 45, 486–490 (1995).

    CAS  Article  Google Scholar 

  50. 50

    Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

    CAS  Article  Google Scholar 

  51. 51

    Carbon, S. et al. AmiGO: online access to ontology and annotation data. Bioinformatics 25, 288–289 (2009).

    CAS  Article  Google Scholar 

  52. 52

    Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).

    CAS  Article  Google Scholar 

  53. 53

    Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Irazoqui, J. E., Ng, A., Xavier, R. J. & Ausubel, F. M. Role for β-catenin andHOX transcription factors in Caenorhabditis elegans and mammalian hostepithelial-pathogen interactions. Proc. Natl Acad. Sci. USA 105, 17469–17474 (2008).

    CAS  Article  Google Scholar 

  55. 55

    Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).

    CAS  Article  Google Scholar 

  56. 56

    O’Rourke, E. J., Soukas, A. A., Carr, C. E. & Ruvkun, G. C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab. 10, 430–435 (2009).

    Article  Google Scholar 

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We thank G. Karsenty, D. Moore, H. Zoghbi, S. Colamarino, E. Abrams, D. Sabatini and R. Zoncu for critical reading of the manuscript. We thank G. Diez-Roux for critical reading of the manuscript, helpful discussions and support in manuscript preparation. We are also grateful to D. Medina, C. Spampanato and F. Annunziata for their contribution. We thank A. Soukas for help with the oil red O staining of C. elegans. We acknowledge the support of the Italian Telethon Foundation grant numbers TGM11CB6 (C.S., R.D.C. and A.B) and TGM11SB1 (A.C. and D.D.B.); the Beyond Batten Disease Foundation (C.S., F.V., T.H. and A.B.); European Research Council Advanced Investigator grant no. 250154 (A.B.); March of Dimes #6-FY11-306 (A.B.); US National Institutes of Health (R01-NS078072) (A.B.). This work was supported in part by grants from the US National Institutes of Health (R01-HL51586) to L.C. and the Diabetes and Endocrinology Research Center (P30-DK079638, L.C.) and the Mouse Metabolism Core (P.K.S.) at Baylor College of Medicine. T.J.K. is in part supported by the Cancer Prevention and Research Institute of Texas (RP110390). O.V. was funded by a Fund for Medical Discovery postdoctoral fellowship from the Massachusetts General Hospital. This study was funded in part by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM101056-01 to J.E.I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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C.S., G.M., P.K.S., F.V., O.V., T.H., R.D.C., A.C., D.P., T.J.K. and A.C.W. performed the experiments. D.D.B. supervised bioinformatic analyses. J.E.I. supervised the C. elegans experiments, L.C. supervised the metabolic studies, and A.B. and C.S. designed the overall study and supervised the work. All authors discussed the results and made substantial contributions to the manuscript.

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Correspondence to Carmine Settembre or Andrea Ballabio.

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Settembre, C., De Cegli, R., Mansueto, G. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol 15, 647–658 (2013).

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