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 impact 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-CoA in the hypothalamus, and, thirdly, whether changes in hypothalamic AMPK signaling are associated to BAT thermogenesis during pregnancy. Our data indicate that in pregnant rats, the hypothalamic fatty acid pathway shows an overall state that should lead to anorexia and elevated brown adipose tissue (BAT) thermogenesis: decreased activities of AMP-activated protein kinase (AMPK), FAS and carnitine palmitoyltransferase 1 (CPT1), coupled to increased acetyl-CoA carboxylase (ACC) 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 (pSTAT3) and phospho-forkhead box O1 (pFoxO1). 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.