Abstract
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.
Highlights
Estrogens, especially estradiol (E2), have potent effects on energy intake [1, 2]
We focused on the nucleus tractus solitarius (NTS), a key brain stem nucleus for food intake regulation, as a target area because previous studies have demonstrated that the NTS is critical to E2’s anorectic action [18] and that brain-derived neurotrophic factor (BDNF) acts in this area to influence food intake and body weight [12]
Compelling evidence suggests that E2 exerts its catabolic action indirectly via enhancing the strength of other signals implicated in the direct control of food intake and energy expenditure
Summary
Especially estradiol (E2), have potent effects on energy intake [1, 2]. In female mammals, including rodents and humans, eating decreases during the peri-ovulatory period of the ovarian cycle due to the preceding and coincident increases in circulating estrogen [3]. Disruption of rat ovarian cycling by ovariectomy (OVX) significantly increases daily food intake and promotes body weight gain, and these can be normalized by cyclic E2 replacement that mimics a normal ovarian cycle [4] Despite these well-known anorectic effects of E2, the mechanisms underlying E2’s catabolic actions are largely unknown. Mice with central TrkB gene deletion have increased body weight, an effect that is significantly more robust in females than in males [17]. These findings highlight the need for focused examination of the role of BDNF/TrkB receptor signaling in mediating E2’s anorectic effects
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