RESUMEN
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.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Anorexia/inducido químicamente , Regulación de la Temperatura Corporal/efectos de los fármacos , Hipotálamo/metabolismo , Malonil Coenzima A/farmacología , Tejido Adiposo Pardo/fisiología , Animales , Ácidos Grasos/biosíntesis , Femenino , Regulación Enzimológica de la Expresión Génica , Metabolismo de los Lípidos/fisiología , Malonil Coenzima A/metabolismo , Ovariectomía , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo Pardo/metabolismo , Estradiol/farmacología , Hipotálamo/efectos de los fármacos , Termogénesis/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/química , Animales , Metabolismo Energético/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Hipotálamo/enzimología , Hipotálamo/metabolismo , Ovario/lesiones , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Sistema Nervioso Simpático/metabolismoRESUMEN
Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.