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 -