Effect of metabolic fuel availability on fertility varies with reproductive state Alfonso Abizaid*, Shelina Jafferali, Joe-Guillaume Pelletier, Barbara Woodside Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, Canada H4B 1R6 Received 7 December 2000; received in revised form 20 March 2001; accepted 2 May 2001 Abstract A 48-h fast extends the estrous cycle of virgin rats and, when instituted on days 13 and 14 postpartum (pp), prolongs lactational infertility. We investigated the ability of 2-deoxy-D-glucose (2DG) alone or combined with mercaptoacetate (MA) to mimic these effects of fasting. In Experiment 1, we monitored estrous cyclicity in virgin rats receiving 800, 1200, or 1600 mg/kg/day of 2DG during metestrus and diestrus. In Experiment 2, we assessed the effects of 2DG (1600 mg/kg/day) given on days 13 and 14 pp, on the duration of lactational infertility. In Experiment 3, the combined effects of 2DG (1600, 2000, or 2400 mg/kg/day) and MA (180 mg/kg/day) on the length of lactational diestrus were evaluated. 2DG was sufficient to extend the estrous cycle of virgin rats, but neither 2DG alone nor given with MA prolonged the length of lactational diestrus. Results suggest that lactating rats are less sensitive than virgin rats to the effects of metabolic fuel inhibition on fertility. These data are discussed in relation to the hormonal state of the dam as well as in relation to the effects of these drugs on lactational performance. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Food deprivation; Lactation; 2DG; Fertility 1. Introduction Reproduction in female mammals is profoundly affected by changes in energy balance. Situations in which the energetic demands of a female are higher than the energy available result in a suppression of reproductive function until energy balance is once again attained [2,3,17,39,40]. The relationship between reduced energy availability and inhibition of the reproductive axis has been observed in many species of female mammals, both in the wild and in captivity [2 –4,12,13,15]. In laboratory rodents, it has been demonstrated that acute periods of fasting (48 h) result in a disruption of the estrous cycle [2,16,17]. Similarly, lactating rats nursing eight pups and having free access to food have a lactational diestrus that lasts approximately 19 – 20 days; but if rats nursing the same number of pups are food-deprived for 48 h starting on day 13 postpartum (pp), their lactational diestrus is extended to about 25–27 days [43]. This effect is not surprising considering that the 48-h fast occurs at a time in which the pups grow at a very rapid rate and still derive all their nutrients from their mother’s milk. The suppressive effects of the 48-h fast on the reproductive axis of both cycling and lactating rats have been attributed to a suppres- sion of circulating levels of luteinizing hormone (LH) that may stem from a suppression of gonadotropin-releasing hormone (GnRH) release from the hypothalamus [39,42]. It has been suggested that the regulation of reproductive function by nutritional factors is mediated primarily by changes in the availability of metabolic fuels for oxidation [27,39,40]. For example, acute treatment with pharmaco- logical agents like 2-deoxy-D-glucose (2DG, a glucose oxidation inhibitor) to female rats leads to a suppression of LH pulses that is similar to that seen during food deprivation [5,6,18,19]. In addition, the estrous cycle of female rats and hamsters is disrupted after chronic 2DG treatment [26,27]. The effects of metabolic fuel inhibitors on the reproductive axis of lactating rats have not been assessed, but it has been reported that the length of lacta- tional diestrus is prolonged by a restriction in caloric intake and not by a restriction in the intake of any one specific macronutrient [42]. These data are consistent with the 0031-9384/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII:S0031-9384(01)00557-1 * Corresponding author. Tel.: +1-514-848-2228; fax: +1-514-848- 4545. E-mail address: alfabiz@vax2.concordia.ca (A. Abizaid). Physiology & Behavior 74 (2001) 77 – 83