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Estradiol-Dependent Decrease in the Orexigenic Potency of Ghrelin in Female Rats

¹ Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio
² Department of Nutrition, University of North Carolina at Greensboro, Greensboro, North Carolina
³ Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
⁴ Department of Physiology Life Sciences, University of Southern Illinois School of Medicine, Carbondale, Illinois
⁵ Department of Psychiatry, Weill Medical College of Cornell University, New York, New York
⁶ Institute for Animal Science, ETH Zürich, Schwerzenbach, Switzerland

Address correspondence and reprint requests to Deborah J. Clegg, Department of Psychiatry, University of Cincinnati, P.O. Box 670559, Cincinnati, OH 45267-0559. E-mail: debbie.clegg{at}uc.edu

Abbreviations: AgRP, Agouti-related protein; Arc, arcuate nucleus; CT, average threshold cycle; ER, estrogen receptor; GSHR, growth hormone secretagogue receptor; i3vt, intra–third ventricular; ip, intraperitoneal; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; OVX, ovariectomized or ovariectomy

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and before meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in the action of ghrelin, we assessed the effects of exogenous ghrelin in intact male and female rats, the effects of exogenous ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide expression in rats and on food intake and weight gain in transgenic mice lacking the ghrelin receptor (Ghsr^–/– mice). Male and OVX female rats were significantly more sensitive than intact female rats to the orexigenic effects of both centrally (intra–third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is likely to be estradiol dependent because E2 attenuated the orexigenic action of ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr^–/– mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol. In addition, following OVX, there was an increase in plasma ghrelin that was temporally associated with increased food intake, body weight, and hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight.

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