Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Noelia Martínez-Sánchez, Patricia Seoane-Collazo, Cristina Contreras, Luis Varela, Joan Villarroya, Eva Rial-Pensado, Xabier Buqué, Igor Aurrekoetxea, Teresa C. Delgado, Rafael Vázquez-Martínez, Ismael González-García, Juan Roa, Andrew J. Whittle, Beatriz Gomez-Santos, Vidya Velagapudi, Y. C.Loraine Tung, Donald A. Morgan, Peter J. Voshol, Pablo B. Martínez de Morentin, Tania López-GonzálezLaura Liñares-Pose, Francisco Gonzalez, Krishna Chatterjee, Tomás Sobrino, Gema Medina-Gómez, Roger J. Davis, Núria Casals, Matej Orešič, Anthony P. Coll, Antonio Vidal-Puig, Jens Mittag, Manuel Tena-Sempere, María M. Malagón, Carlos Diéguez, María Luz Martínez-Chantar, Patricia Aspichueta, Kamal Rahmouni, Rubén Nogueiras, Guadalupe Sabio, Francesc Villarroya, Miguel López

Research output: Contribution to journalArticleScientificpeer-review

156 Citations (Scopus)


Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism. Martínez-Sánchez et al. show that thyroid hormones act in the hypothalamus to regulate hepatic lipogenesis and brown fat lipid oxidation via the parasympathetic and sympathetic nervous systems. These peripheral effects are orchestrated by two distinct signaling pathways in the VMH, JNK1 and ceramides/ER stress, which are under AMPK control.
Original languageEnglish
Pages (from-to)212-229.e12
JournalCell Metabolism
Issue number1
Publication statusPublished - 5 Jul 2017
MoE publication typeA1 Journal article-refereed


  • AMPK
  • BAT
  • ER stress
  • JNK1
  • SF1
  • VMH
  • Male
  • Thyroid Hormones
  • Liver
  • Adipose Tissue
  • Mitogen-Activated Protein Kinase 8
  • Triiodothyronine
  • Signal Transduction
  • Mice, Inbred C57BL
  • Rats
  • Lipid Metabolism
  • Rats, Sprague-Dawley
  • Hypothalamus
  • Animals
  • Thermogenesis
  • Energy Metabolism


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