Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats

Pablo B Martínez de Morentin, Ricardo Lage, Ismael González-García, Francisco Ruíz-Pino, Luís Martins, Diana Fernández-Mallo, Rosalía Gallego, Johan Fernø, Rosa Señarís, Asish K Saha, Sulay Tovar, Carlos Diéguez, Rubén Nogueiras, Manuel Tena-Sempere, Miguel López

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51 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)947-960
Number of pages14
Issue number3
Early online date23 Dec 2014
Publication statusPublished - Mar 2015

Bibliographical note

Funding: The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant agreement No. 281854, the ObERStress European Research Council project (M.L.), and 245009, the Neurofast project (R.N., C.D., and M.L.); Xunta de Galicia (M.L., 2012-CP070; R.N., EM 2012/039, 2012-CP069, and PIE13/00024); Junta de Andalucía (M.T.S., P08-CVI-03788); Instituto de Salud Carlos III (ISCIII) (M.L., PI12/01814); MINECO cofunded by the FEDER Program of EU (M.T.S., BFU2011–25021; R.N., BFU2012–35255; C.D., BFU2011–29102); The Frank Mohn Foundation, Bergen (J.F.); and the and the US National Institutes of Health (A.K.S., DK-19514 and DK-67509). L.M. is a recipient of a fellowship from Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/65379/2009); I.G.-G. is a recipient of a fellowship from Ministerio de Educación, Cultura y Deporte (FPU12/01827). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. - See more at:


  • AMP-Activated Protein Kinases
  • Adipose Tissue, Brown
  • Animals
  • Anorexia
  • Body Temperature Regulation
  • Fatty Acids
  • Female
  • Gene Expression Regulation, Enzymologic
  • Hypothalamus
  • Lipid Metabolism
  • Malonyl Coenzyme A
  • Ovariectomy
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley


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