title: Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats.
abstract: During gestation, hyperphagia is necessary to cope with the metabolic demands of embryonic development. There were three main aims of this study: Firstly, to investigate the effect of pregnancy on hypothalamic fatty acid metabolism, a key pathway for the regulation of energy balance; secondly, to study whether pregnancy induces resistance to the anorectic effect of fatty acid synthase (FAS) inhibition and accumulation of malonyl-coenzyme A (CoA) in the hypothalamus; and, thirdly, to study whether changes in hypothalamic AMPK signaling are associated with brown adipose tissue (BAT) thermogenesis during pregnancy. Our data suggest that in pregnant rats, the hypothalamic fatty acid pathway shows an overall state that should lead to anorexia and elevated BAT thermogenesis: decreased activities of AMP-activated protein kinase (AMPK), FAS, and carnitine palmitoyltransferase 1, coupled with increased acetyl-CoA carboxylase function with subsequent elevation of malonyl-CoA levels. This profile seems dependent of estradiol levels but not prolactin or progesterone. Despite the apparent anorexic and thermogenic signaling in the hypothalamus, pregnant rats remain hyperphagic and display reduced temperature and BAT function. Actually, pregnant rats develop resistance to the anorectic effects of central FAS inhibition, which is associated with a reduction of proopiomelanocortin (POMC) expression and its transcription factors phospho-signal transducer and activator of transcription 3, and phospho-forkhead box O1. This evidence demonstrates that pregnancy induces a state of resistance to the anorectic and thermogenic actions of hypothalamic cellular signals of energy surplus, which, in parallel to the already known refractoriness to leptin effects, likely contributes to gestational hyperphagia and adiposity.
authors.affiliation: Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) (P.B.M.d.M., R.L., I.G.-G., L.M., D.F.M., R.S., S.T., C.D., R.N., M.L.), University of Santiago de Compostela (USC)-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela 15782, Spain; Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBERobn) (P.B.M.d.M., R.L., I.G.-G., F.R.-P., L.M., D.F.M., S.T., C.D., R.N., M.T.-S., M.L.), Santiago de Compostela 15706, Spain; Department of Cell Biology, Physiology and Immunology (F.R.-P., M.T.-S.), University of Córdoba, Córdoba 14004, Spain; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofía (F.R.-P., M.T.-S.), Córdoba 14004, Spain; Department of Morphological Sciences (R.G.), School of Medicine, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; Department of Clinical Science (J.F.), K. G. Jebsen Center for Diabetes Research, University of Bergen, Bergen, N-5021, Norway; and Diabetes Research Unit, EBRC-827 (A.K.S.), Boston Medical Center, Boston, Massachusetts 02118.
authors.forename: Pablo B
authors.initials: PB
authors.lastname: Martínez de Morentin
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lage
authors.forename: Ismael
authors.initials: I
authors.lastname: González-García
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruíz-Pino
authors.forename: Luís
authors.initials: L
authors.lastname: Martins
authors.forename: Diana
authors.initials: D
authors.lastname: Fernández-Mallo
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.forename: Rosa
authors.initials: R
authors.lastname: Señarís
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
authors.forename: Sulay
authors.initials: S
authors.lastname: Tovar
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000502:physiology; D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D001833:Body Temperature Regulation / Q000187:drug effects*; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007031:Hypothalamus / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008316:Malonyl Coenzyme A / Q000378:metabolism / Q000494:pharmacology*; D010052:Ovariectomy; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005227:Fatty Acids; D008316:Malonyl Coenzyme A; D055372:AMP-Activated Protein Kinases