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; 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

doi:10.1016/j.cmet.2017.06.014

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

VTT Technical Research Centre of Finland

Research output: Contribution to journal › Article › Scientific › peer-review

91 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 language	English
Pages (from-to)	212-229.e12
Journal	Cell Metabolism
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2017.06.014
Publication status	Published - 5 Jul 2017
MoE publication type	A1 Journal article-refereed

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

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Martínez-Sánchez, N., Seoane-Collazo, P., Contreras, C., Varela, L., Villarroya, J., Rial-Pensado, E., Buqué, X., Aurrekoetxea, I., Delgado, T. C., Vázquez-Martínez, R., González-García, I., Roa, J., Whittle, A. J., Gomez-Santos, B., Velagapudi, V., Tung, Y. C. L., Morgan, D. A., Voshol, P. J., Martínez de Morentin, P. B., ... 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.

@article{7d6d6376675a4d5792afe92d3e89454b,

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

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.",

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",

author = "Noelia Mart{\'i}nez-S{\'a}nchez and Patricia Seoane-Collazo and Cristina Contreras and Luis Varela and Joan Villarroya and Eva Rial-Pensado and Xabier Buqu{\'e} and Igor Aurrekoetxea and Delgado, {Teresa C.} and Rafael V{\'a}zquez-Mart{\'i}nez and Ismael Gonz{\'a}lez-Garc{\'i}a and Juan Roa and Whittle, {Andrew J.} and Beatriz Gomez-Santos and Vidya Velagapudi and Tung, {Y. C.Loraine} and Morgan, {Donald A.} and Voshol, {Peter J.} and {Mart{\'i}nez de Morentin}, {Pablo B.} and Tania L{\'o}pez-Gonz{\'a}lez and Laura Li{\~n}ares-Pose and Francisco Gonzalez and Krishna Chatterjee and Tom{\'a}s Sobrino and Gema Medina-G{\'o}mez and Davis, {Roger J.} and N{\'u}ria Casals and Matej Ore{\v s}i{\v c} and Coll, {Anthony P.} and Antonio Vidal-Puig and Jens Mittag and Manuel Tena-Sempere and Malag{\'o}n, {Mar{\'i}a M.} and Carlos Di{\'e}guez and Mart{\'i}nez-Chantar, {Mar{\'i}a Luz} and Patricia Aspichueta and Kamal Rahmouni and Rub{\'e}n Nogueiras and Guadalupe Sabio and Francesc Villarroya and Miguel L{\'o}pez",

note = "Funding Information: We dedicate this work to the bright memory of our colleague and friend Rafael V{\'a}zquez-Mart{\'i}nez. The research leading to these results has received funding from the European Community{\textquoteright}s Seventh Framework Programme ( FP7/2007-2013 ) under grant agreements n° 260464 – the OBECAN project (G.S.) and n° 281854 – the ObERStress project (M.L.), Xunta de Galicia (F.G., ED431C-2016-025 and ED341D-R2016-032 ; R.N., 2015-CP080 and 2016-PG057 ; M.L., 2015-CP079 and 2016-PG068 ), Junta de Andaluc{\'i}a (M.T.-S., P12-FQM-01943 ), Gobierno Vasco-Departamento de Salud (M.L.M.-C., 2013111114 ), EITB (M.L.M.-C., BIO15/CA/014 ), Ayudas para apoyar grupos de investigaci{\'o}n del sistema Universitario Vasco (P.A., IT971-16 ), Generalitat de Catalunya (N.C., 2014SGR465 ), Fundaci{\'o} La Marat{\'o} de TV3 (N.C., 87/C/2016 ), Instituto de Salud Carlos III co-funded by FEDER (F.G., RD16/0008/0003 ; M.L.M.-C., PIE14/00031 ), Ministerio de Econom{\'i}a y Competitividad (MINECO) co-funded by the FEDER Program of EU (N.C., SAF2014-52223-C2-2-R ; M.T.-S., BFU2014-57581-P -P ; M.M.M., BFU2013-44229-R ; C.D., BFU2014-55871-P ; M.L.M.-C., SAF2014-54658-R ; P.A., SAF2015-64352-R ; R.N., BFU2015-70664R ; G.S., SAF2013-43506-R ; F.V., SAF2014 55725 ; M.L., SAF2015-71026-R ; G.M., M.M.M., F.V., and M.L., BFU2015-70454-REDT/Adipoplast ), Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (T.C.D. and M.L.M.-C.), Medical Research Council (MRC) Metabolic Diseases Unit (A.J.W., Y.C.L.T., A.P.C., and A.V.-P., MRC_MC_UU_12012/1 and MRC_UU_12015/5 ), MRC Programme Grant (Y.C.L.T. and A.P.C., G9824984 ), MRC Disease Model Core (P.J.V. and A.V.-P.), Wellcome Trust Investigator Award (K.C., 095564/Z/11/Z ), Deutsche Forschungsgemeinschaft (J.M., Mi1242/2-1 ), NIH (R.J.D., DK107220 and DK112698 ; K.R., HL084207 ), American Heart Association (K.R., EIA#14EIA18860041 ) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center (K.R.), EFSD/Lilly Programme (G.S., GIM/EFS1601 ), Astra Zeneca Foundation (R.N.) and the European Foundation for the Study of Diabetes (R.N.), and Atresmedia Corporaci{\'o}n (M.L.). C.C. is recipient of a Sara Borrell Contract ( CD14/0007 ) from ISCIII ; J.V. is recipient of a Juan de la Cierva Contract ( IJDC-2014-19681 ) from MINECO ; E.R.-P. is recipient of a fellowship from MINECO ( BES-2015-072743 ); I.G.-G. is recipient of a fellowship from MINECO ( FPU12/01827 ); L.L.-P. is recipient of a fellowship from Xunta de Galicia ( ED481A-2016/094 ); T.C.D. is supported by AECC ( AIO2013 ); T.S. is recipient of a Miguel Servet Contract ( CP12/03121 ) from ISCIII ; R.J.D. is an Investigator of the Howard Hughes Medical Institute; and F.V. is an ICREA Academia researcher, Generalitat de Catalunya. The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05 ) and the CNIC is supported by the MINECO and the Pro-CNIC Foundation . Pro-CNIC Foundation is a Severo Ochoa Center of Excellence ( MINECO award SEV-2015-0505 ). The technical assistance of Luz Casas in performing the in situ hybridization, Maria Jesus Sanchez-Tapia in performing genotyping analyses, and Tuulikki Sepp{\"a}nen-Laakso and Ulla Lahtinen in performing lipidomics analyses is cordially appreciated. CIBER de Fisiopatolog{\'i}a de la Obesidad y Nutrici{\'o}n and CIBER de Enfermedades hep{\'a}ticas y Digestivas are initiatives of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2017 The Authors Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2017",

month = jul,

day = "5",

doi = "10.1016/j.cmet.2017.06.014",

language = "English",

volume = "26",

pages = "212--229.e12",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "1",

}

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 journal › Article › Scientific › peer-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

N1 - Funding Information: We dedicate this work to the bright memory of our colleague and friend Rafael Vázquez-Martínez. The research leading to these results has received funding from the European Community’s Seventh Framework Programme ( FP7/2007-2013 ) under grant agreements n° 260464 – the OBECAN project (G.S.) and n° 281854 – the ObERStress project (M.L.), Xunta de Galicia (F.G., ED431C-2016-025 and ED341D-R2016-032 ; R.N., 2015-CP080 and 2016-PG057 ; M.L., 2015-CP079 and 2016-PG068 ), Junta de Andalucía (M.T.-S., P12-FQM-01943 ), Gobierno Vasco-Departamento de Salud (M.L.M.-C., 2013111114 ), EITB (M.L.M.-C., BIO15/CA/014 ), Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (P.A., IT971-16 ), Generalitat de Catalunya (N.C., 2014SGR465 ), Fundació La Marató de TV3 (N.C., 87/C/2016 ), Instituto de Salud Carlos III co-funded by FEDER (F.G., RD16/0008/0003 ; M.L.M.-C., PIE14/00031 ), Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (N.C., SAF2014-52223-C2-2-R ; M.T.-S., BFU2014-57581-P -P ; M.M.M., BFU2013-44229-R ; C.D., BFU2014-55871-P ; M.L.M.-C., SAF2014-54658-R ; P.A., SAF2015-64352-R ; R.N., BFU2015-70664R ; G.S., SAF2013-43506-R ; F.V., SAF2014 55725 ; M.L., SAF2015-71026-R ; G.M., M.M.M., F.V., and M.L., BFU2015-70454-REDT/Adipoplast ), Asociación Española contra el Cáncer (T.C.D. and M.L.M.-C.), Medical Research Council (MRC) Metabolic Diseases Unit (A.J.W., Y.C.L.T., A.P.C., and A.V.-P., MRC_MC_UU_12012/1 and MRC_UU_12015/5 ), MRC Programme Grant (Y.C.L.T. and A.P.C., G9824984 ), MRC Disease Model Core (P.J.V. and A.V.-P.), Wellcome Trust Investigator Award (K.C., 095564/Z/11/Z ), Deutsche Forschungsgemeinschaft (J.M., Mi1242/2-1 ), NIH (R.J.D., DK107220 and DK112698 ; K.R., HL084207 ), American Heart Association (K.R., EIA#14EIA18860041 ) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center (K.R.), EFSD/Lilly Programme (G.S., GIM/EFS1601 ), Astra Zeneca Foundation (R.N.) and the European Foundation for the Study of Diabetes (R.N.), and Atresmedia Corporación (M.L.). C.C. is recipient of a Sara Borrell Contract ( CD14/0007 ) from ISCIII ; J.V. is recipient of a Juan de la Cierva Contract ( IJDC-2014-19681 ) from MINECO ; E.R.-P. is recipient of a fellowship from MINECO ( BES-2015-072743 ); I.G.-G. is recipient of a fellowship from MINECO ( FPU12/01827 ); L.L.-P. is recipient of a fellowship from Xunta de Galicia ( ED481A-2016/094 ); T.C.D. is supported by AECC ( AIO2013 ); T.S. is recipient of a Miguel Servet Contract ( CP12/03121 ) from ISCIII ; R.J.D. is an Investigator of the Howard Hughes Medical Institute; and F.V. is an ICREA Academia researcher, Generalitat de Catalunya. The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05 ) and the CNIC is supported by the MINECO and the Pro-CNIC Foundation . Pro-CNIC Foundation is a Severo Ochoa Center of Excellence ( MINECO award SEV-2015-0505 ). The technical assistance of Luz Casas in performing the in situ hybridization, Maria Jesus Sanchez-Tapia in performing genotyping analyses, and Tuulikki Seppänen-Laakso and Ulla Lahtinen in performing lipidomics analyses is cordially appreciated. CIBER de Fisiopatología de la Obesidad y Nutrición and CIBER de Enfermedades hepáticas y Digestivas are initiatives of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2017 The Authors Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

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

UR - http://www.scopus.com/inward/record.url?scp=85032692524&partnerID=8YFLogxK

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 -