title: A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance.
abstract: AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.
authors.affiliation: 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.
authors.forename: Luís
authors.initials: L
authors.lastname: Martins
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seoane-Collazo
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Contreras
authors.affiliation: 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.
authors.forename: Ismael
authors.initials: I
authors.lastname: González-García
authors.affiliation: 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.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.affiliation: 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.
authors.forename: Francisco
authors.initials: F
authors.lastname: González
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Zalvide
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: 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.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain; Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, 14004 Córdoba, Spain; FiDiPro Program, Department of Physiology, University of Turku, Kiinamyllynkatu10, 20520 Turku, Finland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.affiliation: 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.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism; D000068797:Orexins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics*; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C578627:Hcrtr1 protein, rat; D064446:Orexin Receptors; D000068797:Orexins; C493475:Slc17a6 protein, rat; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D055372:AMP-Activated Protein Kinases