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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Silva, J.E. Thyroid hormone control of thermogenesis and energy balance. Thyroid 5, 481–492 (1995).
Coppola, A. et al. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. 5, 21–33 (2007).
Herwig, A., Ross, A.W., Nilaweera, K.N., Morgan, P.J. & Barrett, P. Hypothalamic thyroid hormone in energy balance regulation. Obes. Facts 1, 71–79 (2008).
Pijl, H. et al. Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability. J. Clin. Endocrinol. Metab. 86, 5848–5853 (2001).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Volpe, J.J. & Kishimoto, Y. Fatty acid synthetase of brain: development, influence of nutritional and hormonal factors and comparison with liver enzyme. J. Neurochem. 19, 737–753 (1972).
Gnoni, G.V., Landriscina, C., Ruggiero, F.M. & Quagliariello, E. Effect of hyperthyroidism on lipogenesis in brown adipose tissue of young rats. Biochim. Biophys. Acta 751, 271–279 (1983).
Blennemann, B., Leahy, P., Kim, T.S. & Freake, H.C. Tissue-specific regulation of lipogenic mRNAs by thyroid hormone. Mol. Cell. Endocrinol. 110, 1–8 (1995).
Cachefo, A. et al. Hepatic lipogenesis and cholesterol synthesis in hyperthyroid patients. J. Clin. Endocrinol. Metab. 86, 5353–5357 (2001).
Park, S.H. et al. Effects of thyroid state on AMP-activated protein kinase and acetyl-CoA carboxylase expression in muscle. J. Appl. Physiol. 93, 2081–2088 (2002).
Winder, W.W. et al. Long-term regulation of AMP-activated protein kinase and acetyl-CoA carboxylase in skeletal muscle. Biochem. Soc. Trans. 31, 182–185 (2003).
Branvold, D.J. et al. Thyroid hormone effects on LKB1, MO25, phospho-AMPK, phospho-CREB and PGC-1α in rat muscle. J. Appl. Physiol. 105, 1218–1227 (2008).
Irrcher, I., Walkinshaw, D.R., Sheehan, T.E. & Hood, D.A. Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo. J. Appl. Physiol. 104, 178–185 (2008).
Morini, P., Conserva, A.R., Lippolis, R., Casalino, E. & Landriscina, C. Differential action of thyroid hormones on the activity of certain enzymes in rat kidney and brain. Biochem. Med. Metab. Biol. 46, 169–176 (1991).
Blennemann, B., Moon, Y.K. & Freake, H.C. Tissue-specific regulation of fatty acid synthesis by thyroid hormone. Endocrinology 130, 637–643 (1992).
Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).
Gao, S. et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl. Acad. Sci. USA 104, 17358–17363 (2007).
Kola, B. et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One. 3, e1797 (2008).
López, M. et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389–399 (2008).
Andrews, Z.B. et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).
Loftus, T.M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).
Hu, Z., Cha, S.H., Chohnan, S. & Lane, M.D. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc. Natl. Acad. Sci. USA 100, 12624–12629 (2003).
Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat. Med. 9, 756–761 (2003).
Lam, T.K., Schwartz, G.J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579–584 (2005).
Wolfgang, M.J. et al. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. USA 103, 7282–7287 (2006).
López, M. et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 55, 1327–1336 (2006).
Chakravarthy, M.V. et al. Brain fatty acid synthase activates PPAR-α to maintain energy homeostasis. J. Clin. Invest. 117, 2539–2552 (2007).
Lam, T.K. Neuronal regulation of homeostasis by nutrient sensing. Nat. Med. 16, 392–395 (2010).
Dulloo, A.G. Biomedicine. A sympathetic defense against obesity. Science 297, 780–781 (2002).
Commins, S.P., Watson, P.M., Levin, N., Beiler, R.J. & Gettys, T.W. Central leptin regulates the UCP1 and ob genes in brown and white adipose tissue via different β-adrenoceptor subtypes. J. Biol. Chem. 275, 33059–33067 (2000).
Tong, Q. et al. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 5, 383–393 (2007).
Chatterjee, V.K. et al. Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors. J. Clin. Invest. 87, 1977–1984 (1991).
Lage, R. et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 24, 2670–2679 (2010).
Hagenfeldt, L., Wennlung, A., Felig, P. & Wahren, J. Turnover and splanchnic metabolism of free fatty acids in hyperthyroid patients. J. Clin. Invest. 67, 1672–1677 (1981).
Beylot, M. et al. Lipolytic and ketogenic fluxes in human hyperthyroidism. J. Clin. Endocrinol. Metab. 73, 42–49 (1991).
Riis, A.L. et al. Elevated regional lipolysis in hyperthyroidism. J. Clin. Endocrinol. Metab. 87, 4747–4753 (2002).
Kahn, B.B., Alquier, T., Carling, D. & Hardie, D.G. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005).
Lage, R., Diéguez, C., Vidal-Puig, A. & López, M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol. Med. 14, 539–549 (2008).
Plum, L. et al. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat. Med. 15, 1195–1201 (2009).
Belgardt, B.F. et al. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab. 7, 291–301 (2008).
Pocai, A. et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006).
He, W., Lam, T.K., Obici, S. & Rossetti, L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat. Neurosci. 9, 227–233 (2006).
Sangiao-Alvarellos, S. et al. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J. Neuroendocrinol. 22, 543–556 (2010).
Niijima, A., Rohner-Jeanrenaud, F. & Jeanrenaud, B. Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue. Am. J. Physiol. 247, R650–R654 (1984).
Holt, S.J., Wheal, H.V. & York, D.A. Hypothalamic control of brown adipose tissue in Zucker lean and obese rats. Effect of electrical stimulation of the ventromedial nucleus and other hypothalamic centres. Brain Res. 405, 227–233 (1987).
Halvorson, I., Gregor, L. & Thornhill, J.A. Brown adipose tissue thermogenesis is activated by electrical and chemical (L-glutamate) stimulation of the ventromedial hypothalamic nucleus in cold-acclimated rats. Brain Res. 522, 76–82 (1990).
McCrimmon, R.J. et al. Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57, 444–450 (2008).
Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
van Marken Lichtenbelt, W.D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Virtanen, K.A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Skarulis, M.C. et al. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J. Clin. Endocrinol. Metab. 95, 256–262 (2010).
Viollet, B. et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111, 91–98 (2003).
Long, Y.C. & Zierath, J.R. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116, 1776–1783 (2006).
Costanzo-Garvey, D.L. et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 10, 366–378 (2009).
Dzamko, N. et al. AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J. Biol. Chem. 285, 115–122 (2010).
Rahmouni, K. et al. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J. Clin. Invest. 114, 652–658 (2004).
Nogueiras, R. et al. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet induced obesity. J. Neurosci. 29, 5916–5925 (2009).
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).
C.L. is an employee of AstraZeneca Research and Development and holds stock in AstraZeneca Research and Development.
About this article
Cite this article
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). https://doi.org/10.1038/nm.2207
Progress in Lipid Research (2021)
Molecular and Cellular Endocrinology (2021)
κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance
International Journal of Molecular Sciences (2021)
Cell Metabolism (2020)
Molecular Metabolism (2020)