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

  1. Deborah J. Clegg1,
  2. Lynda M. Brown2,
  3. Jeffrey M. Zigman3,
  4. Christopher J. Kemp1,
  5. April D. Strader4,
  6. Stephen C. Benoit1,
  7. Stephen C. Woods1,
  8. Michela Mangiaracina5 and
  9. Nori Geary56
  1. 1Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio
  2. 2Department of Nutrition, University of North Carolina at Greensboro, Greensboro, North Carolina
  3. 3Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
  4. 4Department of Physiology Life Sciences, University of Southern Illinois School of Medicine, Carbondale, Illinois
  5. 5Department of Psychiatry, Weill Medical College of Cornell University, New York, New York
  6. 6Institute for Animal Science, ETH Zürich, Schwerzenbach, Switzerland
  1. 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

Abstract

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 24 January 2007. DOI: 10.2337/db06-0015.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 16, 2007.
    • Received January 4, 2006.
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  1. Published online before print January 24, 2007, doi: 10.2337/db06-0015 Diabetes April 2007 vol. 56 no. 4 1051-1058
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