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Decreased Gonadotropin-Releasing Hormone Neuronal Activity Is Associated with Decreased Fertility and Dysregulation of Food Intake in the Female GPR-4 Transgenic Rat

Departments of Physiology (F.G., S.E.l.F., R.I.W., M.F.D.) and Obstetrics, Gynecology and Reproductive Sciences (R.I.W., M.E.M.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Richard I. Weiner, Department of Obstetrics, Gynecology and Reproductive Sciences, 513 Parnassus Avenue, HSW1475, Box 0556, University of California, San Francisco, California 94143. E-mail: weinerr{at}obgyn.ucsf.edu.

Expression of a cAMP-specific phosphodiesterase in GnRH neurons in the GPR-4 transgenic rat resulted in decreased LH levels and pulse frequency and diminished fertility. We have characterized changes in fertility, adiposity, and reproductive and metabolic hormones with age. Although LH levels were decreased in 3-, 6-, and 9-month-old GPR-4 females relative to wild-type (WT) controls, GPR-4 females did not become anovulatory until 6 months of age. No differences were observed in FSH, estradiol, or androstenedione levels in 3-, 6-, or 9-month-old GPR-4 and WT females. At 9 months of age, GPR-4 females had significantly increased abdominal and sc fat depot weights that were associated with increased leptin and insulin levels not observed in WT females. We tested the hypothesis that metabolic changes observed at 9 months of age were the result of dysregulation of the mechanisms controlling energy balance. Two-month-old female GPR-4 rats placed on a high-energy diet gained weight at a rate significantly greater than WT females and, after 24 d, developed the same metabolic phenotype observed in 9-month-old GRP-4 females (increased abdominal and sc fat associated with elevated leptin and insulin concentrations). Overeating did not correlate with changes in estradiol or androstenedione levels. We conclude that decreased GnRH neuronal activity is closely associated with decreased reproductive function and dysregulation of food intake.