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

51 Citations (Scopus)

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. 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
Volume26
Issue number1
DOIs
Publication statusPublished - 5 Jul 2017
MoE publication typeA1 Journal article-refereed

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

Keywords

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

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.e12. 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.e12.
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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. Mart{\'i}nez-S{\'a}nchez 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.",
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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.e12. 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.e12.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

AU - Martínez-Sánchez, Noelia

AU - Seoane-Collazo, Patricia

AU - Contreras, Cristina

AU - Varela, Luis

AU - Villarroya, Joan

AU - Rial-Pensado, Eva

AU - Buqué, Xabier

AU - Aurrekoetxea, Igor

AU - Delgado, Teresa C.

AU - Vázquez-Martínez, Rafael

AU - González-García, Ismael

AU - Roa, Juan

AU - Whittle, Andrew J.

AU - Gomez-Santos, Beatriz

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

PY - 2017/7/5

Y1 - 2017/7/5

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. 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.

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. 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.

KW - AMPK

KW - BAT

KW - ER stress

KW - JNK1

KW - SF1

KW - VMH

KW - Male

KW - Thyroid Hormones/metabolism

KW - Liver/metabolism

KW - Adipose Tissue, Brown/metabolism

KW - Mitogen-Activated Protein Kinase 8/metabolism

KW - Triiodothyronine/metabolism

KW - Signal Transduction

KW - Mice, Inbred C57BL

KW - Rats

KW - Lipid Metabolism

KW - Rats, Sprague-Dawley

KW - Hypothalamus/metabolism

KW - Animals

KW - Thermogenesis

KW - Energy Metabolism

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U2 - 10.1016/j.cmet.2017.06.014

DO - 10.1016/j.cmet.2017.06.014

M3 - Article

AN - SCOPUS:85032692524

VL - 26

SP - 212-229.e12

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -

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.e12. https://doi.org/10.1016/j.cmet.2017.06.014