Administration of leptin during undernutrition improves reproductive function, but whether this occurs at the level of the brain, pituitary, or gonads is not yet clear. The present study tested the hypothesis that one important mechanism is the control of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Our approach was to determine if leptin could prevent the marked suppression of pulsatile luteinizing hormone (LH) secretion which occurs during fasting. Leptin (3 µg/g i.p.; three times/48 h) or vehicle was administered during a 48-hour fast in adult ovariectomized and estrogen-treated ovariectomized rats (n = 5–7/group). LH was measured in blood samples collected every 6 min for 2 h before and after fasting. In vehicle-treated animals, plasma insulin and leptin levels decreased after fasting. As expected, the LH pulse frequency also decreased markedly. When circulating leptin remained artificially elevated during fasting, the suppression of LH pulse frequency did not occur. Leptin treatment maintained a high LH pulse frequency in the presence or absence of estrogen. The finding that leptin modulates LH pulse frequency indicates that this fat-derived hormone conveys information about nutrition to mechanisms which regulate pulsatile gonadotropin-releasing hormone secretion. Because this occurs in the absence of estrogen, the mechanism does not necessarily involve modulation of negative feedback.

Keywords:
Leptin, Gonadotropins, Gonadotropin-releasing hormone, Fasting
1.
Bronson FH: Environmental regulation: Some general principles; in Bronson FH (ed): Mammalian Reproductive Biology. Chicago, University of Chicago Press, 1989, pp 7–27.
2.
Cagampang FRA, Maeda K-I, Yokoyama A, Ota K: Effect of food deprivation on the pulsatile LH release in the cycling and ovariectomized female rat. Horm Metab Res 1990;22:269–272.
3.
Foster DL, Bucholtz DC, Herbosa CG: Metabolic signals and the timing of puberty in sheep; in Plant TM, Lee PA (eds): The Neurobiology of Puberty. Bristol, Journal of Endocrinology Ltd, 1995, pp 243–257.
4.
Schreihofer DA, Amico JA, Cameron JL: Reversal of fasting-induced suppression of luteinizing hormone (LH) secretion in male rhesus monkeys by intragastric nutrient infusion: Evidence for rapid stimulation of LH by nutritional signals. Endocrinology 1993;132:1890–1897.
5.
Wade GN, Schneider JE, Li H-Y: Control of fertility by metabolic cues. Am J Physiol 1996;270:E1–E19.
6.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–432.
7.
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250–252.
8.
Cagampang FRA, Maeda K-I, Tsukamura H, Ohkura S, Ota K: Involvement of ovarian steroids and endogenous opioids in the fasting-induced suppression of pulsatile LH release in ovariectomized rats. J Endocrinol 1991;129:321–328.
9.
Weick RF, Noh KA: Inhibitory effects of estrogen and progesterone on several parameters of pulsatile LH release in the ovariectomized rat. Neuroendocrinology 1984;38:351–356.
10.
Leipheimer RE, Bona-Gallo A, Gallo RV: Influence of estradiol and progesterone on pulsatile LH secretion in 8-day ovariectomized rats. Neuroendocrinology 1986;43:300–307.
11.
Chehab FF, Mounzih K, Lu R, Lim ME: Early onset of reproductive function in normal female mice treated with leptin. Science 1997;275:88–90.
12.
Veldhuis JD, Johnson ML: Cluster analysis: A simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol 1986;250:E486–E493.
13.
Bucholtz DC, Vidwans NM, Herbosa CG, Schillo KK, Foster DL: Metabolic interfaces between growth and reproduction. V. Pulsatile LH secretion is dependent upon glucose availability. Endocrinology 1996;137:601–607.
14.
Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK, Steiner RA: Leptin is a metabolic signal to the reproductive system. Endocrinology 1996;137:3144–3147.
15.
Chehab FF, Lim ME, Ronghue L: Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996;12:318–320.
16.
Mounzih K, Lu R, Chehab FF: Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 1997;138:1190–1193.
17.
Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA: Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 1997;138:855–858.
18.
Zamorano PL, Mahesh VB, De Sevilla LM, Chorich LP, Bhat GK, Brann DW: Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology 1997;65:223–228.
19.
Mangels RA, Jetton AE, Powers JB, Wade GN: Food deprivation and the facilitatory effects of estrogen in female hamsters: The LH surge and locomotor activity. Physiol Behav 1996;60:837–843.
20.
Maeda K-I, Nagatani S, Estacio MA, Tsukamura H: Novel estrogen feedback sites associated with stress-induced suppression of luteinizing hormone secretion in female rats. Cell Mol Neurobiol 1996;16:311–324.
21.
Evans NP, Dahl GE, Glover BH, Karsch FJ: Central regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by estradiol during the period leading up to the preovulatory GnRH surge in the ewe. Endocrinology 1994;134:1806–1811.
22.
Bennett PA, Lindell K, Karlsson C, Carlsson LMS, Carlsson B, Robinson ICAF: Leptin receptor (Ob-R) gene expression and regulation in the rat (abstract OR22-2). 79th Annu Meet Endocrine Soc, Minneapolis 1997.
23.
Mercer JG, Moar KM, Hoggard N: Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. Endocrinology 1998;139:29–34.
24.
Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM: Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 1997;94:1023–1028.
25.
Nagatani S, Bucholtz DC, Murahashi K, Estacio MAC, Tsukamura H, Foster DL, Maeda K-I: Reduction of glucose availability suppresses pulsatile LH release in female and male rats. Endocrinology 1996;137:1166–1170.
26.
Murahashi K, Bucholtz DC, Nagatani S, Tsukahara S, Tsukamura H, Foster DL, Maeda K-I: Suppression of LH pulses by restriction of glucose availability is mediated by sensors in the brain stem. Endocrinology 1996;137:1171–1176.
27.
Dong Q, Lazarus RM, Wong LS, Vellios M, Handelsman DJ: Pulsatile LH secretion in streptozotocin-induced diabetes in the rat. J Endocrinol 1991;131:49–55.
28.
Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ: Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997;389:374–377.
29.
Sivitz WI, Walsh SA, Morgan DA, Thomas MJ, Haynes WG: Effects of leptin on insulin sensitivity in normal rats. Endocrinology 1997;138:3395–3401.
30.
Cagampang FRA, Maeda K-I, Ota K: Involvement of the gastric vagal nerve in the suppression of pulsatile luteinizing hormone release during acute fasting in rats. Endocrinology 1992;130:3003–3006.
31.
Maeda K-I, Cagampang FRA, Coen CW, Tsukamura H: Involvement of the catecholaminergic input to the paraventricular nucleus and of corticotropin-releasing hormone in the fasting-induced suppression of luteinizing hormone release in female rats. Endocrinology 1994;134:1718–1722.
32.
Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS: Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 1997;138:3859–3863.
33.
Schneider JE, Goldman MD, Tang S, Bean B: Leptin, metabolic fuels and reproduction in Syrian hamsters (abstract 166.15). 27th Annu Meet Soc for Neuroscience, New Orleans 1997.
34.
Lumpkin MD, De Paolo LV, Negro-Vilar A: Pulsatile release of follicle-stimulating hormone in ovariectomized rats is inhibited by porcine follicular fluid (inhibin). Endocrinology 1984;114:201–206.
35.
Armario A, Gavalda A, Marti J: Comparison of the behavioral and endocrine response to forced swimming stress in five inbred strains of rats. Psychoneuroendocrinology 1995;20:879–890.
36.
Gomez F, Lahmame A, De Kloet ER, Armario A: Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: Differential responses are mainly located at the adrenocortical level. Neuroendocrinology 1996;63:327–337.
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