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

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

References

  1. 1

    Silva, J.E. Thyroid hormone control of thermogenesis and energy balance. Thyroid 5, 481–492 (1995).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    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).

    CAS  Article  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    Cachefo, A. et al. Hepatic lipogenesis and cholesterol synthesis in hyperthyroid patients. J. Clin. Endocrinol. Metab. 86, 5353–5357 (2001).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Blennemann, B., Moon, Y.K. & Freake, H.C. Tissue-specific regulation of fatty acid synthesis by thyroid hormone. Endocrinology 130, 637–643 (1992).

    CAS  PubMed  Google Scholar 

  16. 16

    Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Gao, S. et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl. Acad. Sci. USA 104, 17358–17363 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Kola, B. et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One. 3, e1797 (2008).

    Article  Google Scholar 

  19. 19

    López, M. et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389–399 (2008).

    Article  Google Scholar 

  20. 20

    Andrews, Z.B. et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Loftus, T.M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).

    CAS  Article  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    Lam, T.K., Schwartz, G.J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579–584 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Wolfgang, M.J. et al. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. USA 103, 7282–7287 (2006).

    CAS  Article  Google Scholar 

  26. 26

    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).

    Article  Google Scholar 

  27. 27

    Chakravarthy, M.V. et al. Brain fatty acid synthase activates PPAR-α to maintain energy homeostasis. J. Clin. Invest. 117, 2539–2552 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Lam, T.K. Neuronal regulation of homeostasis by nutrient sensing. Nat. Med. 16, 392–395 (2010).

    CAS  Article  Google Scholar 

  29. 29

    Dulloo, A.G. Biomedicine. A sympathetic defense against obesity. Science 297, 780–781 (2002).

    Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    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).

    CAS  Article  Google Scholar 

  35. 35

    Beylot, M. et al. Lipolytic and ketogenic fluxes in human hyperthyroidism. J. Clin. Endocrinol. Metab. 73, 42–49 (1991).

    CAS  Article  Google Scholar 

  36. 36

    Riis, A.L. et al. Elevated regional lipolysis in hyperthyroidism. J. Clin. Endocrinol. Metab. 87, 4747–4753 (2002).

    CAS  Article  Google Scholar 

  37. 37

    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).

    CAS  Article  Google Scholar 

  38. 38

    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).

    CAS  Article  Google Scholar 

  39. 39

    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).

    CAS  Article  Google Scholar 

  40. 40

    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).

    CAS  Article  Google Scholar 

  41. 41

    Pocai, A. et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006).

    CAS  Article  Google Scholar 

  42. 42

    He, W., Lam, T.K., Obici, S. & Rossetti, L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat. Neurosci. 9, 227–233 (2006).

    CAS  Article  Google Scholar 

  43. 43

    Sangiao-Alvarellos, S. et al. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J. Neuroendocrinol. 22, 543–556 (2010).

    CAS  Article  Google Scholar 

  44. 44

    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).

    CAS  PubMed  Google Scholar 

  45. 45

    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).

    CAS  Article  Google Scholar 

  46. 46

    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).

    CAS  Article  Google Scholar 

  47. 47

    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).

    CAS  Article  Google Scholar 

  48. 48

    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).

    CAS  Article  Google Scholar 

  49. 49

    van Marken Lichtenbelt, W.D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    CAS  Article  Google Scholar 

  50. 50

    Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    CAS  Article  Google Scholar 

  51. 51

    Virtanen, K.A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

    CAS  Article  Google Scholar 

  52. 52

    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).

    CAS  Article  Google Scholar 

  53. 53

    Viollet, B. et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111, 91–98 (2003).

    CAS  Article  Google Scholar 

  54. 54

    Long, Y.C. & Zierath, J.R. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116, 1776–1783 (2006).

    CAS  Article  Google Scholar 

  55. 55

    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).

    CAS  Article  Google Scholar 

  56. 56

    Dzamko, N. et al. AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J. Biol. Chem. 285, 115–122 (2010).

    CAS  Article  Google Scholar 

  57. 57

    Rahmouni, K. et al. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J. Clin. Invest. 114, 652–658 (2004).

    CAS  Article  Google Scholar 

  58. 58

    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).

    CAS  Article  Google Scholar 

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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).

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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). https://doi.org/10.1038/nm.2207

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