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Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Nature Medicinevolume 16, pages1001–1008 (2010)Cite this article

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Abstract

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

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Figure 1: Energy balance, AMPK pathway and POMC expression.
Figure 2: Effects of chronic central T3 administration.
Figure 3: Effects of central T3 on BAT activation via the SNS.
Figure 4: Effects of genetic ablation of thyroid hormone receptor in the VMH.
Figure 5: Effects of inactivation of hypothalamicde novo lipogenesis.
Figure 6: Effects of selective inactivation of AMPK in the VMH.

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Acknowledgements

We thank M. Adams and A. Whittle for discussion and editing and L. Casas, M. Portas and K. Burling for excellent technical assistance. This work has been supported by grants from the UK Medical Research Council (A.V.-P.: G0802051), the Wellcome Trust (K.C.: 080237; A.V.-P.: 065326/Z/01/Z), Xunta de Galicia (R.G.: PGIDITPXIB20811PR), Fondo Investigaciones Sanitarias (M.L.: PS09/01880), Ministerio de Ciencia e Innovación (C.D.: BFU2008; M.L.: RyC-2007-00211; R.N.: RyC-2008-02219 and SAF2009-07049), the EU (A.V.-P. and M.O.: FP7MITIN; A.V.-P. and M.O.: LSHM-CT-2005–018734; C.D., M.L. and R.N.: Health-F2-2008-223713; M.L.: Marie Curie Program QLK6-CT-2002-51671) and the US National Institutes of Health (A.K.S.: DK-19514 and DK-67509; K.R.: HL-084207). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of Instituto de Salud Carlos III (ISCIII).

Author information

Author notes

  1. Rosalía Gallego, Matej Orešič, Krishna Chatterjee and Asish K Saha: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela (A Coruña), Spain.,

    Miguel López, Luis Varela, María J Vázquez, Carmen R González, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras & Carlos Diéguez

  2. Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) (A Coruña), Spain

    Miguel López, Luis Varela, María J Vázquez, Carmen R González, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras & Carlos Diéguez

  3. Institute of Metabolic Science, Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

    Miguel López, Sergio Rodríguez-Cuenca, Erik Schoenmakers, Krishna Chatterjee & Antonio Vidal-Puig

  4. Technical Research Centre of Finland (VTT), Espoo, Finland

    Vidya R Velagapudi & Matej Orešič

  5. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Donald A Morgan & Kamal Rahmouni

  6. Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Khristofor Agassandian

  7. Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Imperial College, London, UK

    David Carling

  8. Department of Biosciences, AstraZeneca, Research and Development, Mölndal, Sweden

    Christopher Lelliott

  9. Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela (A Coruña), Spain.,

    Rosalía Gallego

  10. Diabetes Research Unit, Boston Medical Center, Boston, Massachusetts, USA

    Asish K Saha

Authors
  1. Miguel López

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  2. Luis Varela

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  3. María J Vázquez

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  4. Sergio Rodríguez-Cuenca

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  5. Carmen R González

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  6. Vidya R Velagapudi

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  7. Donald A Morgan

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  8. Erik Schoenmakers

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  9. Khristofor Agassandian

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  10. Ricardo Lage

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  11. Pablo Blanco Martínez de Morentin

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  12. Sulay Tovar

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  13. Rubén Nogueiras

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  14. David Carling

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  15. Christopher Lelliott

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  16. Rosalía Gallego

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  17. Matej Orešič

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  18. Krishna Chatterjee

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  19. Asish K Saha

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  20. Kamal Rahmouni

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  21. Carlos Diéguez

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  22. Antonio Vidal-Puig

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Contributions

M.L., L.V., M.J.V., S.R.-C., C.R.G., R.L., P.B.M.d.M., S.T. and R.N. performed thein vivo experiments, analytical methods (real-time RT-PCR,in situ hybridization, western blotting and enzymatic assays) and collected and analyzed the data. V.R.V. and M.O. developed analytical platforms and performed and analyzed lipidomic experiments. D.A.M., K.A. and K.R. performed and analyzed the sympathetic nerve activity recording studies. D.C. developed AMPK-DN– and AMPK-CA–encoding adenoviruses. E.S. and K.C. generated TR-DN constructs and validated the TR-DN–encoding adenoviruses. R.G. developed and performed immunohistochemistry and immunofluorescence experiments. A.K.S. developed and performed metabolic analyses. M.L., L.V., S.R.-C., C.L., K.C., K.R., C.D. and A.V.-P. designed the experiments. M.L., S.R.-C., R.N., C.L., K.C., K.R., C.D. and A.V.-P. discussed the manuscript. M.L., C.D. and A.V.-P. coordinated and directed the project. M.L. and A.V.-P. developed the hypothesis and wrote the manuscript.

Corresponding authors

Correspondence toMiguel López orAntonio Vidal-Puig.

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Competing interests

C.L. is an employee of AstraZeneca Research and Development and holds stock in AstraZeneca Research and Development.

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Supplementary Table 1, Supplementary Figures 1–7 and Supplementary Methods (PDF 2357 kb)

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López, M., Varela, L., Vázquez, M.et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance.Nat Med16, 1001–1008 (2010). https://doi.org/10.1038/nm.2207

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