Activation of G protein-coupled estrogen receptor 1 (GPER-1) decreases fluid intake in female rats

Abstract

Estradiol (E2) decreases fluid intake in the female rat and recent studies from our lab demonstrate that the effect is at least in part mediated by membrane-associated estrogen receptors. Because multiple estrogen receptor subtypes can localize to the cell membrane, it is unclear which receptor(s) is generating the anti-dipsogenic effect of E2. The G protein-coupled estrogen receptor 1 (GPER-1) is a particularly interesting possibility because it has been shown to regulate blood pressure; many drinking-regulatory systems play overlapping roles in the control of blood pressure. Accordingly, we tested the hypothesis that activation of GPER-1 is sufficient to decrease fluid intake in female rats. In support of this hypothesis we found that treatment with the selective GPER-1 agonist G1 reduced AngII-stimulated fluid intake in OVX rats. Given the close association between food and fluid intakes in rats, and previous reports suggesting GPER-1 plays a role in energy homeostasis, we tested the hypothesis that the effect of GPER-1 on fluid intake was caused by a more direct effect on food intake. We found, however, that G1-treatment did not influence short-term or overnight food intake in OVX rats. Together these results reveal a novel effect of GPER-1 in the control of drinking behavior and provide an example of the divergence in the controls of fluid and food intakes in female rats.

Selective activation of estrogen receptors, ERα and GPER-1, rapidly decreases food intake in female rats

“…It will be important, therefore, to assess G-1′s effect on short-term food intake in mice that are motivated to eat >1g of chow (i.e., when given a highly palatable food or following a period of food restriction). Finally, our findings are not consistent with a study in which acute administration of G-1 (25–400μg/kg) failed to decrease 24-h food intake in OVX rats (Santollo and Daniels, 2015). However, it should be noted that administration of the same doses of G-1 that failed to alter feeding produced a reliable decrease in angiotensin II-stimulated water intake during a brief (30-min) drinking test (Santollo and Daniels, 2015).…”

“…Finally, our findings are not consistent with a study in which acute administration of G-1 (25–400μg/kg) failed to decrease 24-h food intake in OVX rats (Santollo and Daniels, 2015). However, it should be noted that administration of the same doses of G-1 that failed to alter feeding produced a reliable decrease in angiotensin II-stimulated water intake during a brief (30-min) drinking test (Santollo and Daniels, 2015). Because a much higher dose of estradiol (at least ten-fold) is required to decrease water intake compared to that required to decrease food intake (Asarian and Geary, 2002; Findlay et al, 1979) it is possible that an inhibitory effect of G-1 on feeding may have been observed in the previous study if lower doses of G-1, similar to those used in our and previous studies (Ervin et al, 2015; Kwon et al, 2014) had been administered.…”

“…Imaging studies confirm GPER-1 expression in feeding-related brain areas (Brailoiu et al, 2007; Spary et al, 2013), and some pharmacological studies report an anorexigenic effect of GPER-1. For example, acute administration of the GPER-1 agonist (±)-1-[(3aR*,4S*,9bS*)-4-(6-Bromo-1,3-benzodi-oxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[ c ]quino-lin-8-yl]-ethanone (G-1) decreased daily food intake in OVX guinea pigs (Washburn et al, 2013), but failed to decrease 24-h food intake in OVX rats (Santollo and Daniels, 2015). These discrepant findings, together with emerging reports of functional cross talk between ERα and GPER-1 in cultured cells (Vivacqua et al, 2009) and dopaminergic neurons in mice (Bourque et al, 2015), highlight the need for further studies investigating both the independent and interactive involvement of ERα and GPER-1 in the estrogenic control of food intake.…”

Sex differences in the drinking response to angiotensin II (AngII): Effect of body weight

“…Finally, others have reported no sex difference in fluid intake after AngII treatment (Sun et al, 1996). The reason for the apparent discrepancy is not clear and the lack of an effect in some studies is surprising given the well documented effects estrogens have on inhibiting AngII-stimulated fluid intake (Curtis, 2009; Krause et al, 2003; Santollo and Daniels, 2015a, b; Santollo et al, 2016). Because females have higher levels of circulating estrogens than males, and estrogens tonically inhibit fluid intake (Jarrar et al, 2000; Overpeck et al, 1978; Tarttelin and Gorski, 1971), it is reasonable to predict that AngII-stimulated fluid intake would be greater in males than females, and difficult to reconcile the discrepancy in the literature.…”

Sex differences in angiotensin II‐stimulated fluid intake

“…Researchers in our laboratory have used a pharmacological approach to identify the ER subtypes and pools of ERs that are necessary and sufficient to mediate the anti‐dipsogenic and anti‐natriorexigenic effects of E 2 . We have found that activation of membrane‐associated ERs is sufficient to decrease Ang II‐stimulated water intake, but with a time course that suggests a genomic mechanism of action (Santollo & Daniels, ). We have also shown that different ER subtypes have specific effects on Ang II‐stimulated intake.…”