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.

A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

“…Of note, this mechanism is shared by E2, which also displays a potent central thermogenic action (Martínez de Morentin et al., 2014, Martínez de Morentin et al., 2015). Here we show that male rats did not respond to central BMP8B administration, which might indicate dependence on ovarian steroids, a possibility that was further confirmed by using OVX rats with and without E2 replacement.…”

Hypothalamic AMPK and energy balance

“…Moreover, an adenovirus‐mediated activation of AMPK in the VMH (but not in the ARC) prevented the increase in BAT thermogenesis activity and body weight loss associated induced by centrally administrated E2 . Interestingly, variations in E2 levels during the oestrous cycle and pregnancy were also described to modulate the AMPK pathway, supporting also its physiological importance . Recent studies have demonstrated that bone morphogenetic protein 8B (BMP8B) acts centrally on the modulation of BAT thermogenic activity depending on the activation status of AMPK in the VMH.…”

“…The physiological relevance of these findings is given by the fact that this integrative mechanism is not limited to THs. Indeed, it was demonstrated that the central action of E2, through its binding to oestrogen receptor alpha (ERα), decreased AMPK activity selectively in the VMH, inducing an increase in BAT thermogenic capacity through the SNS in a feeding‐independent manner . Moreover, an adenovirus‐mediated activation of AMPK in the VMH (but not in the ARC) prevented the increase in BAT thermogenesis activity and body weight loss associated induced by centrally administrated E2 .…”

Hypothalamic Lipids: Key Regulators of Whole Body Energy Balance

“…Hypothalamic accumulation of malonyl-CoA after pharmacological or genetic manipulation of key enzymes such as fatty acid synthase, acetyl-CoA carboxylase, and malonyl-CoA decarboxylase promotes downregulation of AgRP/NPY and upregulation of CART/POMC expression, eliciting anorexia [101][102][103][104][105][106][107][108][109] . The metabolic relevance of these enzymes goes beyond the control of feeding, because it has been demonstrated that the surplus of hypothalamic long-chain fatty acid-CoA also impacts peripheral glucose and energy homeostasis through a leptin-independent effect [110][111][112] .…”