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

Miguel López, Luis Varela, María J Vázquez, Sergio Rodríguez-Cuenca, Carmen R González, Vidya R Velagapudi, Donald A Morgan, Erik Schoenmakers, Khristofor Agassandian, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras, David Carling, Christopher Lelliott, Rosalía Gallego, Matej Oresic, Krishna Chatterjee, Asish K Saha, Kamal RahmouniCarlos Diéguez, Antonio Vidal-Puig

Research output: Contribution to journalArticle

422 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1001-1008
Number of pages8
JournalNature Medicine
Volume16
Issue number9
DOIs
Publication statusPublished - Sep 2010

Keywords

  • AMP-Activated Protein Kinases
  • Adipose Tissue, Brown
  • Agouti-Related Protein
  • Animals
  • Arcuate Nucleus of Hypothalamus
  • Cerulenin
  • Energy Metabolism
  • Fatty Acid Synthesis Inhibitors
  • Fatty Acids
  • Hyperphagia
  • Hyperthyroidism
  • Hypothalamus
  • Paraventricular Hypothalamic Nucleus
  • Pro-Opiomelanocortin
  • RNA, Messenger
  • Rats
  • Thermogenesis
  • Thyroid Gland
  • Thyrotropin-Releasing Hormone
  • Thyroxine
  • Triiodothyronine

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    López, M., Varela, L., Vázquez, M. J., Rodríguez-Cuenca, S., González, C. R., Velagapudi, V. R., Morgan, D. A., Schoenmakers, E., Agassandian, K., Lage, R., Martínez de Morentin, P. B., Tovar, S., Nogueiras, R., Carling, D., Lelliott, C., Gallego, R., Oresic, M., Chatterjee, K., Saha, A. K., ... Vidal-Puig, A. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature Medicine, 16(9), 1001-1008. https://doi.org/10.1038/nm.2207