title: GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.
abstract: GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beiroa
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Imbernon
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 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, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Senra
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Herranz
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain Department of Biochemistry and Molecular Biology and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Department of Clinical Science, K.G. Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Salvador
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Escalada
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Dieguez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopez
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain ruben.nogueiras@usc.es.
authors.forename: Ruben
authors.initials: R
authors.lastname: Nogueiras
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D022722:Thermogenesis / Q000187:drug effects*; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D000077270:Exenatide; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases