Oestradiol and Diet Modulate Energy Homeostasis and Hypothalamic Neurogenesis in the Adult Female Mouse

Abstract

Leptin and oestradiol have overlapping functions in energy homeostasis and fertility, and receptors for these hormones are localised in the same hypothalamic regions. Although, historically, it was assumed that mammalian adult neurogenesis was confined to the olfactory bulbs and the hippocampus, recent research has found new neurones in the male rodent hypothalamus. Furthermore, some of these new neurones are leptin-sensitive and affected by diet. In the present study, we tested the hypothesis that diet and hormonal status modulate hypothalamic neurogenesis in the adult female mouse. Adult mice were ovariectomised and implanted with capsules containing oestradiol (E2) or oil. Within each group, mice were fed a high-fat diet (HFD) or maintained on standard chow (STND). All animals were administered i.c.v. 5-bromo-2′-deoxyuridine (BrdU) for 9 days and sacrificed 34 days later after an injection of leptin to induce phosphorylation of signal transducer of activation and transcription 3 (pSTAT3). Brain tissue was immunohistochemically labelled for BrdU (newly born cells), Hu (neuronal marker) and pSTAT3 (leptin sensitive). Although mice on a HFD became obese, oestradiol protected against obesity. There was a strong interaction between diet and hormone on new cells (BrdU+) in the arcuate, ventromedial hypothalamus and dorsomedial hypothalamus. HFD increased the number of new cells, whereas E2 inhibited this effect. Conversely, E2 increased the number of new cells in mice on a STND diet in all hypothalamic regions studied. Although the total number of new leptin-sensitive neurones (BrdU-Hu-pSTAT3) found in the hypothalamus was low, HFD increased these new cells in the arcuate, whereas E2 attenuated this induction. These results suggest that adult neurogenesis in the hypothalamic neurogenic niche is modulated by diet and hormonal status and is related to energy homeostasis in female mice.

Stress-induced alterations in estradiol sensitivity increase risk for obesity in women

“…Leptin receptors are co-localized with ERs in the arcuate nucleus of the hypothalamus indicating a direct mechanism by which E2 increases leptin sensitivity [134]. More recently it was shown in female rodents fed a CDD that E2 decreases diet-induced hypothalamic neurogenesis of leptin-sensitive neurons in the arcuate [135]. A similar study showed that E2 administration in ovariectomized mice normalizes the decreased insulin sensitivity associated with four weeks of HFD exposure [136].…”

Regulation of Body Weight and Metabolism by Tanycyte-Derived Neurogenesis in Young Adult Mice

“…This finding suggests a degree of plasticity that is evolutionarily conserved and likely extends to humans as well (Batailler et al 2013;Dahiya et al 2011;Noguiera et al 2014). Both juvenile and adult mammalian hypothalamus exhibit ongoing neurogenesis that can be regulated by growth and differentiation factors (Pencea et al 2001;Xu et al 2005;Kokoeva et al 2005;Perez-Martin et al 2010;Robins et al 2013b), diet Li et al 2012;McNay et al 2012;Gouaze et al 2013;Bless et al 2014), antidepressants (Sachs and Caron 2014), exercise (Matsuzaki et al 2015), and hormones (Ahmed et al 2008;Bless et al 2014). Although these studies generally agree that levels of constitutive hypothalamic neurogenesis are much lower than those seen in well-characterized neurogenic zones in the adult brain, such as the subventricular zone of the lateral ventricles or the subgranular zone of the lateral hypothalamus , they often report differing effects of extrinsic factors on cell proliferation and neurogenesis in hypothalamus.…”

“…For instance, while multiple groups have reported that long-term administration of HFD inhibits cell proliferation and neurogenesis in hypothalamic parenchyma (Li et al 2012;McNay et al 2012;Gouaze et al 2013;Bless et al 2014), studies investigating acute responses to HFD have reported increased hypothalamic cell proliferation and neurogenesis (Thaler et al 2012;Gouaze et al 2013). Acute HFD administration has also been reported to rapidly induce hypothalamic inflammation, increasing cytokine signaling (Thaler et al 2012).…”

“…Finally, studies of postnatal and adult neurogenesis in the ventrobasal hypothalamus have typically used either only male (Kokoeva et al 2005(Kokoeva et al , 2007McNay et al 2012;Li et al 2012;Sachs and Caron 2014) or only female Bless et al 2014) mice. Neurogenesis in other hypothalamic regions is sexually dimorphic (Ahmed et al 2008), making this but one additional methodological difference that could contribute to differences in the levels, location and dietary regulation of hypothalamic neurogenesis reported in these studies.…”

Effects of glyceollin on mRNA expression in the female mouse brain.

“…17-estradiol (E2) signaling in the hypothalamus, both through classical estrogen receptors ERs (ERα and ERβ) and membrane-associated ERs, including G protein-coupled estrogen receptor 1 (GPER1), is involved in regulating the transcription and release of gonadotrophin releasing hormone (GnRH) and luteinizing hormone (LH) (Petersen et al 2003). E2 also regulates various neural pathways, such as those involved in sexual receptivity (Micevych and Dominguez 2009) and energy homeostasis (Bless et al 2014).…”