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

Nature Cell Biology volume 15, pages 647–658 (2013)Cite this article

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A Corrigendum to this article was published on 01 August 2013

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Abstract

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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Acknowledgements

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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  1. Rossella De Cegli, Gelsomina Mansueto, Pradip K. Saha, Francesco Vetrini and Orane Visvikis: These authors contributed equally to this work

Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy

    Carmine Settembre, Rossella De Cegli, Gelsomina Mansueto, Annamaria Carissimo, Diego Di Bernardo & Andrea Ballabio

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    Carmine Settembre, Francesco Vetrini, Tuong Huynh, Donna Palmer, Tiemo Jürgen Klisch & Andrea Ballabio

  3. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, Texas 77030, USA

    Carmine Settembre, Francesco Vetrini, Tuong Huynh, Tiemo Jürgen Klisch & Andrea Ballabio

  4. Department of Pediatrics, Medical Genetics, Federico II University, Via Pansini 5, 80131 Naples, Italy

    Carmine Settembre & Andrea Ballabio

  5. Division of Diabetes, Department of Medicine, Diabetes and Endocrinology Research Center, Endocrinology and Metabolism, Baylor College of Medicine, Texas 77030, Houston, USA

    Pradip K. Saha & Lawrence Chan

  6. Department of Pediatrics, Program in Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02115, Boston, USA

    Orane Visvikis, Amanda C. Wollenberg & Javier E. Irazoqui

  7. Department of Systems and Computer Science, ‘Federico II’ University of Naples, Naples 80125, Italy

    Diego Di Bernardo

  8. Departments of Molecular and Cellular Biology and Biochemistry, Baylor College of Medicine, USA

    Lawrence Chan

  9. St. Luke’s Episcopal Hospital, Texas 77030, Houston, USA

    Lawrence Chan

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  1. Carmine Settembre
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Contributions

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.

Corresponding authors

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). https://doi.org/10.1038/ncb2718

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