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-González & 21 others Laura 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

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Abstract

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.
Original languageEnglish
Pages (from-to)212-229
Number of pages17
JournalCell Metabolism
Volume26
Issue number1
DOIs
Publication statusPublished - 5 Jul 2017

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AMP-Activated Protein Kinases
Endoplasmic Reticulum Stress
Brown Adipose Tissue
Thyroid Hormones
Lipogenesis
Hypothalamus
Liver
Steroidogenic Factor 1
Parasympathetic Nervous System
Thermogenesis
JNK Mitogen-Activated Protein Kinases
Ceramides
Sympathetic Nervous System
Triiodothyronine
Lipid Metabolism
Lipids
Neurons
Brain
Population

Keywords

  • thyroid hormones
  • VMH
  • SF1
  • AMPK
  • ceramides
  • ER stress
  • JNK1
  • autonomic nervous system
  • liver
  • BAT

Cite this

Martínez-Sánchez, N., Seoane-Collazo, P., Contreras, C., Varela, L., Villarroya, J., Rial-Pensado, E., ... López, M. (2017). Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. Cell Metabolism, 26(1), 212-229. https://doi.org/10.1016/j.cmet.2017.06.014

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. / Martínez-Sánchez, Noelia; Seoane-Collazo, Patricia; Contreras, Cristina; Varela, Luis; Villarroya, Joan; Rial-Pensado, Eva; Buqué, Xabier; Aurrekoetxea, Igor; Delgado, Teresa C.; Vázquez-Martínez, Rafael; González-García, Ismael; Roa, Juan; Whittle, Andrew J.; Gomez-Santos, Beatriz; Velagapudi, Vidya; Tung, Y.C. Loraine; Morgan, Donald A.; Voshol, Peter J.; Martínez de Morentin, Pablo B.; López-González, Tania; Liñares-Pose, Laura; Gonzalez, Francisco; Chatterjee, Krishna; Sobrino, Tomás; Medina-Gómez, Gema; Davis, Roger J.; Casals, Núria; Orešič, Matej; Coll, Anthony P.; Vidal-Puig, Antonio; Mittag, Jens; Tena-Sempere, Manuel; Malagón, María M.; Diéguez, Carlos; Martínez-Chantar, María Luz; Aspichueta, Patricia; Rahmouni, Kamal; Nogueiras, Rubén; Sabio, Guadalupe; Villarroya, Francesc; López, Miguel.

In: Cell Metabolism, Vol. 26, No. 1, 05.07.2017, p. 212-229.

Research output: Contribution to journalArticle

Martínez-Sánchez, N, Seoane-Collazo, P, Contreras, C, Varela, L, Villarroya, J, Rial-Pensado, E, Buqué, X, Aurrekoetxea, I, Delgado, TC, Vázquez-Martínez, R, González-García, I, Roa, J, Whittle, AJ, Gomez-Santos, B, Velagapudi, V, Tung, YCL, Morgan, DA, Voshol, PJ, Martínez de Morentin, PB, López-González, T, Liñares-Pose, L, Gonzalez, F, Chatterjee, K, Sobrino, T, Medina-Gómez, G, Davis, RJ, Casals, N, Orešič, M, Coll, AP, Vidal-Puig, A, Mittag, J, Tena-Sempere, M, Malagón, MM, Diéguez, C, Martínez-Chantar, ML, Aspichueta, P, Rahmouni, K, Nogueiras, R, Sabio, G, Villarroya, F & López, M 2017, 'Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance', Cell Metabolism, vol. 26, no. 1, pp. 212-229. https://doi.org/10.1016/j.cmet.2017.06.014
Martínez-Sánchez N, Seoane-Collazo P, Contreras C, Varela L, Villarroya J, Rial-Pensado E et al. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. Cell Metabolism. 2017 Jul 5;26(1):212-229. https://doi.org/10.1016/j.cmet.2017.06.014
Martínez-Sánchez, Noelia ; Seoane-Collazo, Patricia ; Contreras, Cristina ; Varela, Luis ; Villarroya, Joan ; Rial-Pensado, Eva ; Buqué, Xabier ; Aurrekoetxea, Igor ; Delgado, Teresa C. ; Vázquez-Martínez, Rafael ; González-García, Ismael ; Roa, Juan ; Whittle, Andrew J. ; Gomez-Santos, Beatriz ; Velagapudi, Vidya ; Tung, Y.C. Loraine ; Morgan, Donald A. ; Voshol, Peter J. ; Martínez de Morentin, Pablo B. ; López-González, Tania ; Liñares-Pose, Laura ; Gonzalez, Francisco ; Chatterjee, Krishna ; Sobrino, Tomás ; Medina-Gómez, Gema ; Davis, Roger J. ; Casals, Núria ; Orešič, Matej ; Coll, Anthony P. ; Vidal-Puig, Antonio ; Mittag, Jens ; Tena-Sempere, Manuel ; Malagón, María M. ; Diéguez, Carlos ; Martínez-Chantar, María Luz ; Aspichueta, Patricia ; Rahmouni, Kamal ; Nogueiras, Rubén ; Sabio, Guadalupe ; Villarroya, Francesc ; López, Miguel. / Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. In: Cell Metabolism. 2017 ; Vol. 26, No. 1. pp. 212-229.
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abstract = "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.",
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AU - Martínez-Sánchez, Noelia

AU - Seoane-Collazo, Patricia

AU - Contreras, Cristina

AU - Varela, Luis

AU - Villarroya, Joan

AU - Rial-Pensado, Eva

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AU - Aurrekoetxea, Igor

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AU - Velagapudi, Vidya

AU - Tung, Y.C. Loraine

AU - Morgan, Donald A.

AU - Voshol, Peter J.

AU - Martínez de Morentin, Pablo B.

AU - López-González, Tania

AU - Liñares-Pose, Laura

AU - Gonzalez, Francisco

AU - Chatterjee, Krishna

AU - Sobrino, Tomás

AU - Medina-Gómez, Gema

AU - Davis, Roger J.

AU - Casals, Núria

AU - Orešič, Matej

AU - Coll, Anthony P.

AU - Vidal-Puig, Antonio

AU - Mittag, Jens

AU - Tena-Sempere, Manuel

AU - Malagón, María M.

AU - Diéguez, Carlos

AU - Martínez-Chantar, María Luz

AU - Aspichueta, Patricia

AU - Rahmouni, Kamal

AU - Nogueiras, Rubén

AU - Sabio, Guadalupe

AU - Villarroya, Francesc

AU - López, Miguel

N1 - Open Access funded by European Research Council

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N2 - 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.

AB - 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.

KW - thyroid hormones

KW - VMH

KW - SF1

KW - AMPK

KW - ceramides

KW - ER stress

KW - JNK1

KW - autonomic nervous system

KW - liver

KW - BAT

U2 - 10.1016/j.cmet.2017.06.014

DO - 10.1016/j.cmet.2017.06.014

M3 - Article

VL - 26

SP - 212

EP - 229

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

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