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


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 hypothalamic de novo lipogenesis.
Figure 6: Effects of selective inactivation of AMPK in the VMH.


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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).

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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 the in 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.

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Correspondence to Miguel López or Antonio Vidal-Puig.

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

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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 Med 16, 1001–1008 (2010).

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