Estradiol modulates Kiss1 neuronal response to ghrelin

Abstract

Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-␣ (ER␣) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the co-xpression of GHSR mRNA and ER␣ selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX ϩ E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX ϩ E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ER␣ and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. kisspeptin; hypothalamus; metabolism; growth hormone secretagogue receptor; reproduction IN MAMMALS, THE ABILITY TO REPRODUCE is gated by the availability of energy stores (25,49). Reproduction is metabolically expensive, and during starvation fertility is stopped to conserve energy for basic survival. Accumulating evidence has implicated circulating hormones as a means of transmitting information regarding peripheral energy availability to the central circuitry that controls the reproductive system. Among these metabolic signals is the stomach-derived hormone ghrelin (23,46). Ghrelin was recognized originally for its growth hormonestimulating action, but extensive research has since demonstrated that ghrelin is also a direct regulator of metabolism and energy balance (22,28,55). Ghrelin promotes the storage of lipids as fat, induces glucagon release, and suppresses insulin secretion and sensitivity (4, 5, 47). Interestingly, the effects of ghrelin to increase body weight vary according to the estrogen milieu, as a more pronounced orexigenic effect is observed in females upon ovariectomy (3, 6). In cycling rats, ghrelin stimulation of food intake is observed only in females in diestrus (when estrogen levels are low). Moreover, males treated with estradiol are resistant to the stimulatory effects of ghrelin...

The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction

“…Recently, it has been shown to reduce Kiss1 transcript levels in the hypothalamus. Exogenous injections as well as food restriction induced hyperghrelinemia have been documented to decrease mRNA levels of Kiss1 (Forbes et al 2009, Frazao et al 2014. These findings indicate that ghrelin-induced reduction in hypothalamic Kiss1 expression can be one of the key factors in metabolic deficiency-induced inhibition of the reproductive axis.…”

Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state

“…007914) (36), the R26 enhanced green fluorescent protein (eGFP) (JAX mice, stock no. 004077) (25,26) and db/db (JAX mice, stock no. 000697) mice were kept in the University of Michigan animal facility in a light-(12 h on/off) and temperature-controlled (21-23°C) environment with free access to water and food.…”

Minireview: Metabolic control of the reproductive physiology: Insights from genetic mouse models

“…However, the expression of GHSR has been described in many areas of the hypothalamus, including those implicated in reproductive functioning and regions expressing estrogen receptor α (ERα) (Frazao et al, 2014; Zigman et al, 2006). Interestingly, the orexigenic effects of gherlin is altered depending on the hormonal milieu in female rodents (Clegg et al, 2007).…”

“…Interestingly, the orexigenic effects of gherlin is altered depending on the hormonal milieu in female rodents (Clegg et al, 2007). Accordingly, GHSR mRNA colocalizes with immunoreactive ERα cells within the AVPV, MPO, VMH, and ARH (Frazao et al, 2014). …”

“…Furthermore in the presence of estrogen, ARH GHSR hybridization shows a striking increase from 20% to 80% in ERα cells (Frazao et al, 2014). Because ERα is expressed in the majority of kisspeptin neurons of the AVPV and ARH, our laboratory utilized the Kiss-cre GFP reporter mice to determine the morphological and electrophysiological relationship between kisspeptin cells and ghrelin responsive cells.…”