Central expression and anorectic effect of brain-derived neurotrophic factor are regulated by circulating estradiol levels
Highlights
► Temporal elevation of Bdnf expression coincided with decline in feeding at estrous phase. ► Cyclic estradiol treatment reversed OVX-induced decrease in Bdnf expression. ► BDNF suppressed feeding was significantly greater in estrous rats compared with male rats. ► BDNF suppressed feeding was significantly greater in estradiol-treated OVX rats compared with oil-treated OVX rats.
Introduction
The ovarian hormone estradiol, the primary form of estrogens, is not only a hormone essential for reproduction but is also involved in physiological control of energy balance by potently suppressing food intake in many species including humans (Asarian and Geary, 2006). In women, caloric intake varies across the menstrual cycle. Women tend to eat less during the four-day periovulatory phase of the menstrual cycle when estradiol reaches its peak (Buffenstein et al., 1995, Lissner et al., 1988), and these cyclic changes in feeding are absent in women with anovulatory cycles (Barr et al., 1995). Many postmenopausal women gain body weight due to natural decrease in endogenous estradiol levels (Gambacciani et al., 1997) which can be prevented by estrogen replacement therapy (Gambacciani et al., 1997), implying a role of estradiol in maintenance of body weight. Similarly, cycling female rodents consume different amounts of food across their four-day ovarian cycles, consuming the least during estrus, which occurs right after preovulatory rise in estradiol secretion, and consuming the most during diestrus when estradiol levels are lower (Asarian and Geary, 2002, Asarian and Geary, 2006, Tarttelin and Gorski, 1971), indicating that physiologic estradiol levels are negatively correlated with food intake (Blaustein and Wade, 1976, Brobeck et al., 1947). Disruption of ovarian cycling in rats by ovariectomy (OVX) leads to increases in food intake and weight gain (McElroy and Wade, 1987, Wade, 1975, Wade and Gray, 1979). A cyclic regimen of estradiol replacement at a physiologic dose, designed to mimic the normal changes in plasma estradiol levels across the ovarian cycle, abolishes OVX-induced hyperphagia and normalizes body weight to the levels of gonadally intact rats (Asarian and Geary, 2002). Together, available data suggest that estradiol exerts an inhibitory effect on food intake.
Estradiol suppresses feeding by enhancing the potency of other anorectic signals, such as cholecystokinin (Geary, 2001) and apolipoprotein A-IV (Shen et al., 2010), and by decreasing the potency of orexigenic signals such as melanin-concentrating hormone (Messina et al., 2006) and ghrelin (Clegg et al., 2007). Brain-derived neurotrophic factor (BDNF) could be another putative candidate influenced by estradiol. BDNF is one of the important anorectic signals primarily synthesized by VMH in the hypothalamus (Noble et al., 2011). Acute central administration of BDNF decreases food intake in rats (Wang et al., 2007, Wang et al., 2010). Furthermore, central ventricular BDNF administration suppressed body weight through reductions in meal size and thereby food intake (Spaeth et al., 2012). Mice deficient in BDNF are hyperphagic, and detailed analysis of the feeding patterns of high-fat diet-induced hyperphagia in BDNF deficient mice has revealed that such hyperphagia is mediated by a selective increase in meal size accompanied by a reduced satiety ratio, but no change in meal number (Fox and Byerly, 2004). These findings suggest that BDNF, like estradiol, influences feeding by selectively affecting meal termination and satiation, and therefore affecting the control of meal size.
Two nuclear estrogen receptors (ER), ERα and ERβ, and one membrane ER GPR 30 have been identified. Available evidence supports that ERα mediates the effects of estradiol on energy balance. ERα is abundantly expressed in the arcuate nucleus and the ventromedial nucleus of hypothalamus (VMH) (Chakraborty et al., 2003, Shughrue et al., 1997), two hypothalamic areas associated with feeding and energy homeostasis. In contrast, ERβ expression is barely detectable in the arcuate nucleus or VMH (Shughrue and Merchenthaler, 2001). Instead, high levels of ERβ expression are found in the paraventricular nucleus (PVN) and supraoptic nucleus, the hypothalamic regions with little or no ERα expression (Österlund et al., 1998, Shughrue and Merchenthaler, 2001, Shughrue et al., 1996, Shughrue et al., 1997). Mice deficient in ERα, both males and females, have increased body weight and adiposity (Heine et al., 2000), whereas mice deficient in ERβ have a normal body weight and feeding behavior (Couse and Korach, 1999), suggesting a specific role for ERα, but not ERβ, in mediating the effects of estradiol on energy balance and feeding. Furthermore, inhibition of ERα by RNA interference in the VMH results in severe obesity and metabolic syndrome (Musatov et al., 2007), suggesting the importance of ERα within the VMH in mediating energy homeostasis.
Gene expression and immunoreactivity of BDNF, like those of ERα, are distributed at the highest level in the VMH within the hypothalamus (Xu et al., 2003), the CNS satiety center that regulates anorexia. Bdnf mRNA and BDNF immunoreactivity are also moderately distributed in the medial and ventral parvocellular region of the PVN (Conner et al., 1997). Blurton-Jones et al. (2004) reported the colocalization of BDNF and ERα in the VMH, suggesting possible interactions between BDNF and estradiol in the regulation of feeding.
Thus, the goal of this series of experiments was to determine a possible interaction of estradiol and BDNF in the control of food intake in male and female rats. We hypothesized that Bdnf expression and the anorectic effect of BDNF are regulated by estradiol levels. We first tested whether Bdnf gene expression at the VMH and the PVN was regulated in an estrogen-sensitive manner. We then examined whether estradiol facilitated the anorectic effect of BDNF in gonadally intact male and female rats and in ovariectomized (OVX) rats with or without estradiol replacement. The results collectively suggested a role for estrogen in regulating the effects of BDNF on feeding.
Section snippets
Animals
Adult (12 weeks-old) male and female Long–Evans rats (Harlan, Indianapolis, IN) were housed individually in a temperature-controlled (22 ± 2 °C) vivarium on a 12-h light, 12-h dark cycle (lights on at 0200 h, lights off at 1400 h). Pellet rodent chow (Teklad 7912, Madison, WI) and water were provided ad libitum except as otherwise noted. All animal procedures were approved by the Institutional Animal Care and Use Committee of Miami University OH, and were conducted in strict compliance with the Guide
Experiment 1: Bdnf gene expression of intact male and female rats
The average body weights of male (n = 10) and female (n = 40) rats were 358.48 ± 5.61 g and 244.58 ± 1.09 g, respectively. On average, male and female rats consumed 21.59 ± 1.11 g and 13.71 ± 0.27 g standard rodent chow daily. Thus, age-matched female rats weighed less [t48 = 32.61, P < 0.0001, Cohen's d = 11.77] and consumed less amount of food daily [t48 = 10.24, P < 0.0001, Cohen's d = 3.69] than male rats. Consistent with previous studies (Asarian and Geary, 2002), female rats exhibited cyclic changes in feeding
Discussion
Estradiol exerts an inhibitory effect on feeding that is well characterized in the rat. For example, the preovulatory increase in estradiol secretion in female rats is associated with a phasic decrease in food intake during estrus (Blaustein and Wade, 1976, Drewett, 1973), OVX stimulates sustained hyperphagia that is mediated by decline in estradiol secretion (Wade, 1975), and physiological regimen of estradiol replacement reverses OVX-promoted hyperphagia (Asarian and Geary, 2002). Estradiol
Acknowledgments
We thank Professor Lori Isaacson and Mr. Sean Pugh for providing comments and careful editorial reading. This work was supported by National Institutes of Health DK090823 and American Heart Association SDG4520028 to HS.
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