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Diabetes Publish Ahead of Print published online ahead of print January 24, 2007
DOI: 10.2337/db06-0015
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Original Research

Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats

Deborah J. Clegg1, Lynda M. Brown1, Christopher J. Kemp1, April D. Strader2, Stephen C. Benoit1, Stephen C. Woods1, Michela Mangiaracina3, and Nori Geary3,,4

1Department of Psychiatry, University of Cincinnati, PO Box 670559, Cincinnati, OH 45267-0559
2Department of Physiology Life Sciences, University of Southern Illinois School of Medicine, Carbondale, IL 62901
3Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 1002
4Institute for Animal Science, ETH Zürich, 8603 Schwerzenbach, Switzerland

Correspondence: Debbie.clegg{at}uc.edu

Key Words: NPY • AgRP • food intake • obesity • meal patterns • hunger • sex differences

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and prior to meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in ghrelin's action, we assessed the effects of exogenous ghrelin in intact male and female rats, 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 (3rd-ventricular, i3vt, 0.01, 0.1, 1.0 nmol) and systemically (ip, 3, 6, 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 NPY and AgRP 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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