Central expression and anorectic effect of brain-derived neurotrophic factor are regulated by circulating estradiol levels

Abstract

Estrogens potently suppress food intake. Compelling evidence suggests that estradiol, the primary form of estrogens, reduces food intake by facilitating other anorectic signals. Brain-derived neurotrophic factor (BDNF), like estradiol, appears to suppress food intake by affecting meal size. We hypothesized that estradiol modulates Bdnf expression and the anorectic effect of BDNF. The first goal was to determine whether Bdnf expression was regulated by endogenous estradiol of cycling rats and by cyclic estradiol treatment using ovariectomized rats. Bdnf expression within the ventromedial nucleus of hypothalamus (VMH) was temporally elevated at estrus following the estradiol peak, which coincided with the decline in feeding at this phase of the ovarian cycle. Additionally, food intake and body weight were increased following ovariectomy with a parallel decrease in Bdnf expression in the VMH. All of these alterations were reversed by cyclic estradiol treatment, suggesting that Bdnf expression within the VMH was regulated in an estradiol-dependent manner. The second goal was to determine whether estradiol modulates the anorectic effect of BDNF. Sham-operated estrous rats and ovariectomized rats cyclically treated with estradiol responded to a lower dose of central administration of BDNF to decrease food intake than male rats and oil-treated ovariectomized rats, implying that endogenous estradiol or cyclic estradiol replacement increased the sensitivity to anorectic effect of BDNF. These data indicate that Bdnf expression within the VMH and the anorectic effect of BDNF varied depending on plasma estradiol levels, suggesting that estradiol may regulate BDNF signaling to regulate feeding.

Fig. 1. Cyclic change in daily food intake during female ovarian cycle coincides with changes in circulating estradiol level and Bdnf expression of female rats (Experiment 1)

Food intake (A) and body weight (B) of female rats were measured at individual phases of the ovarian cycle. Data represent mean ± SEM (n = 40). Y-axis of Figs 1A or 1B does not start from zero to clearly show differences in food intake or body weight among different phases of the ovarian cycle. One-way repeated-measures ANOVA followed by Tukey’s posttest indicated that food intake was significantly decreased between proestrus-estrus compared with metestrus-diestrus periods (*, P < 0.05; Fig 1A). Plasma estradiol level (C), and Bdnf mRNA levels in the VMH (D) and in the PVN (E) were measured in male rats and female rats across female ovarian cycle. Data represent mean ± SEM (n = 10). One-way ANOVA followed by Bonferroni’s multiple comparison test compared with Male group was performed. *, P < 0.05.

Fig. 2. Cyclic estradiol replacement normalizes postovariectomy food intake, body weight, circulating estradiol level and VMH Bdnf expression (Experiment 2)

Daily food intake (A) and body weight (B) were measured before and after surgeries from sham-operated rats and OVX rats during five consecutive cycles of treatment with estradiol (2 μg once each fourth day, indicated by arrows) or oil. The pairfed rats (OVX-Oil PF) were provided with the same amount of food consumed by estradiol-treated OVX (OVX-E2) rats each day. Data represent mean ± SEM (n = 10). Y-axis of Figs 2A or 2B does not start from zero to clearly show differences in food intake or body weight among different groups. Two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test compared with Sham-Oil group was performed. *, P < 0.05 OVX-Oil vs. Sham-Oil; #, P < 0.05 OVX-E2 vs. Sham-Oil. Plasma estradiol level (C), and Bdnf mRNA levels in the VMH (D) and in the PVN (E) were measured in sham-operated rats at estrous phase and oil- or estradiol- treated OVX rats one day after oil or estradiol injection. Data represent mean ± SEM (n = 10). One-way ANOVA followed by Bonferroni’s multiple comparison test compared with Sham-Oil group was performed. *, P < 0.05 OVX-Oil or OVX-Oil PF vs. Sham-Oil.

Fig. 3. Endogenous estradiol of sham-operated female rats or cyclic estradiol replacement of OVX rats increases the anorectic effect of BDNF (Experiment 3)

Food intake was measured at 4 h (A) and 24 h (B) after icv administration of BDNF (0, 0.1, or 0.3 μg). Data represent mean ± SEM (n=7–8). A two-way repeated-measures ANOVA followed by Bonferroni’s multiple comparison test compared with 0 μg BDNF was used for analysis of food intake. *, P <0.05 comparing to 0 μg (saline) injection of each group.