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Cell Metab. 2017 Jul 5;26(1):212-229.e12. doi: 10.1016/j.cmet.2017.06.014.

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

Author information

1
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain.
2
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), Barcelona 08028, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona 08026, Spain.
3
Department of Physiology, University of the Basque Country UPV/EHU, Biocruces Research Institute, Barakaldo 48903, Spain.
4
CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Derio, Bizkaia 48160, Spain.
5
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba 14004, Spain.
6
University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
7
VTT Technical Research Centre of Finland, Tietotie 2, Espoo FIN-02044, Finland; Metabolomics Unit, Institute for Molecular Medicine, University of Helsinki, Helsinki FI-00290, Finland.
8
Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
9
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Clinical Neurosciences Research Laboratory, Department of Neurology, Hospital Clínico Universitario, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
10
Department of Surgery, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela 15706, Spain.
11
Clinical Neurosciences Research Laboratory, Department of Neurology, Hospital Clínico Universitario, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
12
University Rey Juan Carlos, Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, Avda. de Atenas s/n, Alcorcon, Madrid 28922, Spain.
13
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
14
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, Barcelona 08195, Spain.
15
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, Finland.
16
University of Lübeck, Internal Medicine I, Center of Brain, Behavior, and Metabolism (CBBM), Ratzeburger Allee 160, Lübeck 23562, Germany.
17
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba 14004, Spain; FiDiPro Program, Department of Physiology, University of Turku, Kiinamyllynkatu 10, Turku FIN-20520, Finland.
18
Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
19
Myocardial Pathophysiology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
20
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), Barcelona 08028, Spain.
21
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain. Electronic address: m.lopez@usc.es.

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.

KEYWORDS:

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

PMID:
28683288
PMCID:
PMC5501726
DOI:
10.1016/j.cmet.2017.06.014
[Indexed for MEDLINE]
Free PMC Article

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