Journal article
Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
Cell metabolism, Vol.26(1), pp.212-229.e12
07/05/2017
DOI: 10.1016/j.cmet.2017.06.014
PMCID: PMC5501726
PMID: 28683288
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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•Central T3 regulates lipogenesis in liver via the parasympathetic nervous system•Central T3 regulates lipid oxidation in BAT via the sympathetic nervous system•Ablation of AMPK in SF1 neurons of the VMH recapitulates the effects of T3•Hypothalamic JNK1 and ceramides/ER stress mediate T3 actions on liver and BAT
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.
Details
- Title: Subtitle
- Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
- Creators
- Noelia Martínez-Sánchez - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainPatricia Seoane-Collazo - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainCristina Contreras - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainLuis Varela - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainJoan Villarroya - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainEva Rial-Pensado - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainXabier Buqué - Department of Physiology, University of the Basque Country UPV/EHU, Biocruces Research Institute, Barakaldo 48903, SpainIgor Aurrekoetxea - Department of Physiology, University of the Basque Country UPV/EHU, Biocruces Research Institute, Barakaldo 48903, SpainTeresa C Delgado - CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Derio, Bizkaia 48160, SpainRafael Vázquez-Martínez - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainIsmael González-García - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainJuan Roa - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainAndrew J Whittle - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKBeatriz Gomez-Santos - Department of Physiology, University of the Basque Country UPV/EHU, Biocruces Research Institute, Barakaldo 48903, SpainVidya Velagapudi - VTT Technical Research Centre of Finland, Tietotie 2, Espoo FIN-02044, FinlandY.C. Loraine Tung - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKDonald A Morgan - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAPeter J Voshol - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKPablo B Martínez de Morentin - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainTania López-González - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainLaura Liñares-Pose - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainFrancisco Gonzalez - Department of Surgery, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainKrishna Chatterjee - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKTomás Sobrino - Clinical Neurosciences Research Laboratory, Department of Neurology, Hospital Clínico Universitario, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainGema Medina-Gómez - University Rey Juan Carlos, Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, Avda. de Atenas s/n, Alcorcon, Madrid 28922, SpainRoger J Davis - Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USANúria Casals - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainMatej Orešič - Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, FinlandAnthony P Coll - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKAntonio Vidal-Puig - University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UKJens Mittag - University of Lübeck, Internal Medicine I, Center of Brain, Behavior, and Metabolism (CBBM), Ratzeburger Allee 160, Lübeck 23562, GermanyManuel Tena-Sempere - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainMaría M Malagón - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainCarlos Diéguez - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainMaría Luz Martínez-Chantar - CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Derio, Bizkaia 48160, SpainPatricia Aspichueta - Department of Physiology, University of the Basque Country UPV/EHU, Biocruces Research Institute, Barakaldo 48903, SpainKamal Rahmouni - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USARubén Nogueiras - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, SpainGuadalupe Sabio - Myocardial Pathophysiology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, SpainFrancesc Villarroya - CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, SpainMiguel López - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.26(1), pp.212-229.e12
- DOI
- 10.1016/j.cmet.2017.06.014
- PMID
- 28683288
- PMCID
- PMC5501726
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- Elsevier Inc
- Grant note
- name: European Community’s Seventh Framework Programme, award: FP7/2007-2013, 260464, 281854; DOI: 10.13039/501100010801, name: Xunta de Galicia, award: ED431C-2016-025, ED341D-R2016-032, 2015-CP080, 2016-PG057, 2015-CP079, 2016-PG068; DOI: 10.13039/501100011011, name: Junta de Andalucía, award: P12-FQM-01943; name: Gobierno Vasco-Departamento de Salud, award: 2013111114; name: EITB, award: BIO15/CA/014; name: Ayudas para apoyar grupos de investigación del sistema Universitario Vasco, award: IT971-16; DOI: 10.13039/501100002809, name: Generalitat de Catalunya, award: 2014SGR465; DOI: 10.13039/100008666, name: Fundació La Marató de TV3, award: 87/C/2016; DOI: 10.13039/501100004587, name: Instituto de Salud Carlos III; DOI: 10.13039/501100008530, name: FEDER, award: RD16/0008/0003, PIE14/00031; DOI: 10.13039/501100003329, name: Ministerio de Economía y Competitividad; name: FEDER Program of EU, award: SAF2014-52223-C2-2-R, BFU2014-57581-P -P, BFU2013-44229-R, BFU2014-55871-P, SAF2014-54658-R, SAF2015-64352-R, BFU2015-70664R, SAF2013-43506-R, SAF2014 55725, SAF2015-71026-R, BFU2015-70454-REDT/Adipoplast; name: Asociación Española contra el Cáncer; name: Medical Research Council, award: MRC_MC_UU_12012/1, MRC_UU_12015/5; name: MRC Programme Grant, award: G9824984; name: MRC Disease Model Core; name: Wellcome Trust Investigator Award, award: 095564/Z/11/Z; DOI: 10.13039/501100001659, name: Deutsche Forschungsgemeinschaft, award: Mi1242/2-1; name: NIH, award: DK107220, DK112698, HL084207; DOI: 10.13039/100000968, name: American Heart Association, award: EIA#14EIA18860041; name: University of Iowa Fraternal Order of Eagles Diabetes Research Center; name: EFSD/Lilly Programme, award: GIM/EFS1601; name: Astra Zeneca Foundation; DOI: 10.13039/501100001648, name: European Foundation for the Study of Diabetes; name: Atresmedia Corporación; DOI: 10.13039/501100004587, name: ISCIII, award: CD14/0007; name: MINECO, award: IJDC-2014-19681; name: MINECO, award: BES-2015-072743; name: MINECO, award: FPU12/01827; DOI: 10.13039/501100010801, name: Xunta de Galicia, award: ED481A-2016/094; DOI: 10.13039/501100002704, name: AECC, award: AIO2013; DOI: 10.13039/501100004587, name: ISCIII, award: CP12/03121; DOI: 10.13039/501100010801, name: Xunta de Galicia, award: ED431G/05; name: MINECO; name: Pro-CNIC Foundation; name: MINECO, award: SEV-2015-0505
- Language
- English
- Date published
- 07/05/2017
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040238102771
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