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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)947-960
Number of pages14
JournalEndocrinology
Volume156
Issue number3
Early online date23 Dec 2014
DOIs
Publication statusPublished - Mar 2015

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Malonyl Coenzyme A
Appetite Depressants
AMP-Activated Protein Kinases
Fatty Acid Synthases
Brown Adipose Tissue
Pregnancy
Hyperphagia
Thermogenesis
Hypothalamus
Fatty Acids
Carnitine O-Palmitoyltransferase
Acetyl-CoA Carboxylase
STAT3 Transcription Factor
Pro-Opiomelanocortin
Adiposity
Anorexia
Leptin
Prolactin
Embryonic Development
Progesterone

Keywords

  • 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

Cite this

Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats. / Martínez de Morentin, Pablo B; Lage, Ricardo; González-García, Ismael; Ruíz-Pino, Francisco; Martins, Luís; Fernández-Mallo, Diana; Gallego, Rosalía; Fernø, Johan; Señarís, Rosa; Saha, Asish K; Tovar, Sulay; Diéguez, Carlos; Nogueiras, Rubén; Tena-Sempere, Manuel; López, Miguel.

In: Endocrinology, Vol. 156, No. 3, 03.2015, p. 947-960.

Research output: Contribution to journalArticle

Martínez de Morentin, PB, Lage, R, González-García, I, Ruíz-Pino, F, Martins, L, Fernández-Mallo, D, Gallego, R, Fernø, J, Señarís, R, Saha, AK, Tovar, S, Diéguez, C, Nogueiras, R, Tena-Sempere, M & López, M 2015, 'Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats', Endocrinology, vol. 156, no. 3, pp. 947-960. https://doi.org/10.1210/en.2014-1611
Martínez de Morentin, Pablo B ; Lage, Ricardo ; González-García, Ismael ; Ruíz-Pino, Francisco ; Martins, Luís ; Fernández-Mallo, Diana ; Gallego, Rosalía ; Fernø, Johan ; Señarís, Rosa ; Saha, Asish K ; Tovar, Sulay ; Diéguez, Carlos ; Nogueiras, Rubén ; Tena-Sempere, Manuel ; López, Miguel. / Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats. In: Endocrinology. 2015 ; Vol. 156, No. 3. pp. 947-960.
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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.",
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T1 - Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats

AU - Martínez de Morentin, Pablo B

AU - Lage, Ricardo

AU - González-García, Ismael

AU - Ruíz-Pino, Francisco

AU - Martins, Luís

AU - Fernández-Mallo, Diana

AU - Gallego, Rosalía

AU - Fernø, Johan

AU - Señarís, Rosa

AU - Saha, Asish K

AU - Tovar, Sulay

AU - Diéguez, Carlos

AU - Nogueiras, Rubén

AU - Tena-Sempere, Manuel

AU - López, Miguel

N1 - 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: http://press.endocrine.org/doi/10.1210/en.2014-1611#sthash.mKeyG62X.dpuf

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

KW - AMP-Activated Protein Kinases

KW - Adipose Tissue, Brown

KW - Animals

KW - Anorexia

KW - Body Temperature Regulation

KW - Fatty Acids

KW - Female

KW - Gene Expression Regulation, Enzymologic

KW - Hypothalamus

KW - Lipid Metabolism

KW - Malonyl Coenzyme A

KW - Ovariectomy

KW - Pregnancy

KW - Rats

KW - Rats, Sprague-Dawley

U2 - 10.1210/en.2014-1611

DO - 10.1210/en.2014-1611

M3 - Article

C2 - 25535827

VL - 156

SP - 947

EP - 960

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 3

ER -