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. 2017 Sep 19;8(48):84028-84038.
doi: 10.18632/oncotarget.21062. eCollection 2017 Oct 13.

BDNF/TrkB Signaling Mediates the Anorectic Action of Estradiol in the Nucleus Tractus Solitarius

Free PMC article

BDNF/TrkB Signaling Mediates the Anorectic Action of Estradiol in the Nucleus Tractus Solitarius

Ling Shen et al. Oncotarget. .
Free PMC article


Although compelling evidence indicates that estradiol (E2) acts in the nucleus tractus solitarius (NTS) to reduce food intake, the underlying mechanisms are largely unknown. We now report that estrogen's anorectic action occurs through enhancing the strength of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (TrkB) signaling in the NTS. Intra-4th-ventricular administration of a low dose of BDNF reduced food intake to a greater extent in ovariectomized (OVX) rats cyclically treated with E2 than in vehicle-treated OVX rats, implying that cyclic E2 replacement increases BDNF's satiating potency. OVX significantly decreased bdnf gene expression in the NTS, and this was reversed by cyclic replacement of E2. Treatment of cultured primary neuronal cells from embryonic rat brainstem with E2 or PPT (ERα agonist), but not with DPN (ERβ agonist), significantly increased bdnf mRNA levels, indicating that ERα is the primary receptor mediating E2's stimulatory effect on bdnf gene expression. Administration of the selective TrkB antagonist, ANA-12, directly into the NTS significantly attenuated E2-induced reductions of food intake and body weight gain in OVX rats, indicating that TrkB receptor activation is necessary for E2's anorectic effect. Finally, relative to controls, OVX mice with bdnf gene knockdown specifically in the NTS had a blunted feeding response to E2. These data collectively imply that BDNF/TrkB receptor signaling in the NTS is a downstream mediator of E2 in the control of energy intake.

Keywords: BDNF; TrkB receptor; estrogen; food intake; obesity.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.


Figure 1
Figure 1. Cyclic E2 replacement enhances the anorectic effect of BDNF in OVX rats
(A) Food intake was measured at 6 h and 24 h, and (B) body weight was measured at 24 h after i4vt administration of BDNF (0.5 or 1 μg). Data expressed as the mean ± SEM, n = 7–8 rats per group. *P < 0.05; **P < 0.01, compared with aCSF controls; #P < 0.05, compared with the OVX rats receiving 0.5 μg of BDNF.
Figure 2
Figure 2. Comparison of bdnf mRNA levels in the NTS measured by qPCR
(A) Bdnf mRNA levels in the NTS of female rats were significantly higher than those of male rats, and bdnf gene expression in female rats at estrus was significantly higher than those of rats at diestrus. Mean ± SEM, n = 7–8. *P < 0.05 and **P < 0 .01, compared with male rats; #P < 0.05, compared to rats at diestrus. Di, diestrus phase; E, estrous phase. (B) The decreased bdnf mRNA levels induced by OVX were restored by E2 replacement, but not by pair-feeding. The pair-fed (PF) rats were provided with the same amount of food consumed by E2-treated OVX (OVX + E2) rats each day. *P < 0.05, compared with sham oil-treated rats; #P < 0.05, compared with OVX oil-treated rats; &P < 0.05, compared with OVX + pair-fed rats.
Figure 3
Figure 3. Bdnf gene expression is stimulated by E2 or an ERa, but not an ERb, agonist in cultured embryonic brainstem cells
(A–C) The cells were stained with antibodies against BDNF (red) and MAP-2 (green). The co-localization of BDNF with MAP-2, a neuronal marker, is reflected as an orange color. (D) The cells were treated for 24 h with 10 nM E2, PPT, or DPN, respectively. Both E2 and PPT, but not DPN, significantly stimulated bdnf gene expression, compared with vehicle controls. (E) To determine whether a nongenomic mechanism is involved, the cultured neuronal cells were treated with E2-BSA or vehicle. No significant difference was found between E2-BSA and vehicle-treated cells. Mean ± SE; n = 3. **P < 0.01.
Figure 4
Figure 4. Antagonism of TrkB receptor signaling in the NTS attenuated E2's anorectic action
The highly TrkB-selective receptor antagonist, ANA-12, was used to determine whether the NTS TrkB receptor mediates the reduction of food intake induced by acute treatment of E2. (A) Photomicrograph illustrating the injection site (NTS), as identified by 0.2 μl of methylene blue. AP, area postrema; cc, central canal; DMN, dorsal motor nucleus of the vagus. Scale 100 μm. (B and C) E2 significantly reduced food intake and body weight gain, and these effects were significantly attenuated by pre-administration of a dose of 3 μg ANA-12. Mean ± SEM, n = 6–8. *P < 0.05, compared with vehicle-treated rats; #P < 0.05, compared with E2-treated rats.
Figure 5
Figure 5. Bdnf gene knockdown specifically in the NTS diminished E2's anorectic effect
(A) Schematic drawing depicting the location of the NTS of mouse brain. (B) Representative micrograph showing expression of green fluorescent protein (GFP) of AAV8 virus in the NTS of bdnfflox/flox mice as determined under fluorescence microscopy. (C) qPCR evaluation of bdnf mRNA levels in the NTS punches of AAV-Cre- and AAV-GFP-injected bdnfflox/flox mice. Mean ± S.E., n = 15–16 per group. *P < 0.05, compared with the OVX mice treated with AAV-GFP virus. (DF) Comparison of food intake, body weight and body fat mass among OVX mice with bdnf gene knockdown specifically in the NTS and OVX control mice, both receiving cyclic treatment of E2 or oil. (GI) Comparison of blood glucose, plasma insulin and E2 levels among the 4 groups. Mean ± S.E., n = 7–8. *P < 0.05; **P < 0.01, compared with the OVX mice treated with oil; #P < 0.05, compared with OVX AAV8-GFP-control mice treated with E2.

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    1. Asarian L, Geary N. Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol. 2013;305:R1215–67. - PMC - PubMed
    1. Geary N, Lovejoy L. Sex differences in energy metabolism, obesity and eating behavior. In: Becker J, editor. Sex on the brain: from genes to behavior. New York: Oxford Publishers; 2008. pp. 253–74.
    1. Asarian L, Geary N. Modulation of appetite by gonadal steroid hormones. Philos Trans R Soc Lond B Biol Sci. 2006;361:1251–63. - PMC - PubMed
    1. Asarian L, Geary N. Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats. Horm Behav. 2002;42:461–71. - PubMed
    1. Eckel LA. Estradiol: a rhythmic, inhibitory, indirect control of meal size. Physiol Behav. 2004;82:35–41. - PubMed

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