The receptor basis of estradiol's anorexigenic effect

It is well established that the ovarian hormone estradiol exerts its diverse actions primarily via the two classic estrogen receptors (ERs), ERalpha and ERbeta. While available data suggest that ERalpha plays an important role (14, 15, 17, 21), the time course over which selective activation of ERalpha inhibits food intake differs from that observed following similar administration of a non-selective ER agonist (estradiol benzoate) and thus requires further study. At present, the contribution of ERbeta to the estrogenic control of food intake remains equivocal. Thus, the goals of the current research were to investigate the time course over which selective activation of ERalpha decreases food intake in ovariectomized rats and whether ERbeta is sufficient or necessary for estradiol's anorexigenic effect. Experiment 1 revealed that acute administration of the ERalpha agonist PPT produced a rapid, dose-dependent decrease in food intake that was detected within 2 h and persisted for up to 21-h. In contrast, acute administration of a range of doses of the ERbeta agonist DPN failed to influence food intake. Experiment 2 revealed that DPN failed to modulate PPT's anorexigenic effect. Experiment 3 revealed that the anorexigenic effect of estradiol benzoate (EB) was not attenuated by co-administration of the ERbeta antagonist PHTPP. Experiment 4 revealed that the ERbeta agonist DPN reliably decreased anxiety-like behavior in the elevated plus maze and that this action of DPN was attenuated by co-administration of the ERbeta antagonist PHTPP. These positive findings confirm the involvement of ERbeta in mediating estradiol's anxiolytic effect and provide critical evidence that the same dose of these compounds that failed to alter food intake in our feeding tests effectively targeted (activated or blocked) ERbeta. Taken together, these data demonstrate that PPT exerts a rapid anorexigenic effect that appears to occur with minimal or no delay. Because this time course appears to preclude the involvement of nuclear ERs, which function to alter gene transcription following a long (12-24 h) latency, PPTs rapid anorexigenic effect suggests the involvement of membrane ERalpha signaling events. Additionally, our data provide compelling evidence that ERbeta is neither sufficient nor necessary for estradiol's anorexigenic effect. The null findings associated with DPN and PHTPP are not likely due to insufficient targeting of ERbeta as both drugs altered anxiety-like behavior, suggesting that appropriate doses were used to probe ERbeta's involvement in the estrogenic control of food intake.