Food-restricted Females Research Articles

Gender-specific programmed hepatic lipid dysregulation in intrauterine growth-restricted offspring

Intrauterine growth restriction demonstrates increased risk of adult metabolic syndrome. The associated hyperlipidemia results from obesity or programmed metabolic abnormalities. Because lipid homeostasis is regulated by the liver, we hypothesized that hepatic structure and lipid content in intrauterine growth restriction would reflect a primary lipid dysfunction. From 10 days to term gestation, control pregnant rats received ad libitum diet; study rats were 25% food-restricted (FR). All dams received ad libitum diet throughout lactation. At 3 weeks of age, hepatic lobule size and lipid profile of the pups were determined. At 3 weeks of age, body and liver weights of the pups were comparable with controls, although with reduced hepatic lobule size. FR males had increased hepatic triglyceride and cholesterol content with elevated sterol regulatory element-binding protein-1c, fatty acid synthase, and lipoprotein lipase expression; FR females exhibited decreased hepatic cholesterol levels. Plasma lipid levels were unchanged in FR males and females. Developmental programming results in sex-dependent altered lipid metabolism with increased risk in males.

Maternal food restriction delays weaning in the guinea pig, Cavia porcellus

In mammals, the duration of lactation varies much more than other life history parameters in relation to body mass, both within and between species. The causes of this variation are poorly understood and seem to result from varying conditions of mothers and young. We studied the effect of long-term maternal food restriction on litter mass at birth, duration of lactation and offspring development in the precocial guinea pig. Mild experimental food restriction during reproduction resulted in prolonged nursing behaviour of mothers. Evidence for a threshold mass at weaning was, however, equivocal. In the guinea pig, benefits of prolonged lactation prove hard to understand, because nutritional benefits are minor. Independently of maternal food regime, pups terminated suckling attempts several days after mothers ceased nursing behaviour. The time between the last nursing behaviour and the last suckling attempts was not longer in litters with higher need, that is, in litters of food-restricted females, than in litters of females fed ad libitum. Under food restriction, mothers maintained their own body mass, leading in pups to lower mass at birth, reduced postnatal growth and lower body mass at maturity. Guinea pig mothers appear to be selected to value their own condition more than that of a litter. We suggest that lengthening of the nursing period under poor conditions is a life history response primarily of precocial mammals.

Effects of leptin administration on lactational infertility in food-restricted rats depend on milk delivery.

Leptin administration has been shown to prevent the disruptive effects of acute food deprivation on reproductive function in cycling females and lactating females. We examined the ability of intracerebroventricular leptin administration to ameliorate the effects of food restriction for the first 2 wk postpartum on length of lactational infertility. Leptin administration did not reduce the effects of food restriction on reproductive function at either time period (days 8-15 and 15-22 postpartum) or dose (1 and 10 microg/day) administered. Because of the sharp contrast between these results and the ability of leptin to offset the effects of acute food deprivation in lactating rats, the remaining studies investigated the possible causes of this difference. Both central and peripheral leptin administration eliminated food deprivation-induced prolongation of lactational infertility, suggesting that neither route of administration nor dose was a factor. However, we noticed that, whereas chronically food-restricted females continue to deliver milk to their young, acutely food-deprived females do not. To test the hypothesis that the continued energetic drain of milk production and delivery might prevent the ability of exogenous leptin administration to eliminate the effects of undernutrition, leptin was administered to food-restricted, lactating rats prevented from delivering milk. In this situation intracerebroventricular leptin treatment completely eliminated the effects of food restriction on lactational infertility, suggesting that leptin contributes to the maintenance of reproductive function via two pathways: direct binding in the central nervous system and through increasing the availability of oxidizable metabolic fuels.

An evolutionarily conserved form of gonadotropin-releasing hormone coordinates energy and reproductive behavior.

GnRH is the master neuropeptide that coordinates and regulates reproduction in all vertebrates and in some nonvertebrate species. Sixteen forms of GnRH have been isolated in brain. In the vast majority of species, two or more forms occur in anatomically and developmental distinct neuronal populations. In mammalian brain, two GnRH forms, mammalian (GnRH-I) and chicken-II (GnRH-II), exist. The distribution and functions of GnRH-I have been well characterized and intensively studied. However, the function of GnRH-II, which is the most evolutionarily conserved form of GnRH, has been elusive. Here we demonstrate that in a primitive mammal, the musk shrew (Suncus murinus), GnRH-II activates mating behavior in nutritionally challenged females within a few minutes after administration. In addition GnRH-II immunoreactive cell numbers and fibers increase in food-restricted females. Furthermore, GnRH type II receptor immunoreactivity was detected in musk shrew brain in regions associated with mating behavior. Our results lead us to hypothesize that the role of the evolutionarily conserved GnRH-II peptide is to coordinate reproductive behavior as appropriate to the organism's energetic condition.

Mating behavior is controlled by acute changes in metabolic fuels.

Mild food restriction for 48 h inhibits mating behavior in female musk shrews (Suncus murinus). However, mating behavior is restored after a 90-min feeding bout. In this series of experiments, we examined the role of metabolic fuels in this behavioral restoration. First, drugs reported to block glycolysis or fatty acid oxidation were given 2 h before mating. Both treatments inhibited mating in food-restricted females that were refed after treatment. Blood glucose levels were assessed in females that were fed ad libitum, food restricted, or food restricted and refed for 90 min. Food restriction significantly lowered blood glucose compared with ad libitum feeding or food restriction in combination with 90 min of refeeding. However, neither glucose nor fat alone could substitute for food and promote mating behavior in food-restricted females. In addition, analysis of ketone bodies and body composition in females demonstrated low or undetectable levels of these energy substrates. Our data suggest that musk shrews have relatively little stored energy. Therefore, female musk shrews rely on continuous food intake and monitor multiple cues acutely, including glucose availability and fatty acid oxidation. This ensures that mating does not occur when adequate energy is unavailable.

Acute Re-Feeding Reverses Food Restriction-Induced Hypothalamic-Pituitary-Gonadal Axis Deficits1

Undernutrition has well-established effects on female reproduction. Here we describe the effects of food restriction on aspects of the hypothalamic-pituitary-gonadal (HPG) axis in the female musk shrew. We determined that acute re-feeding reverses deficits brought on by food restriction. Two days of food restriction led to an increase in proGnRH immunoreactive cells in the preoptic area relative to ad libitum-fed controls (AL). This increase was reversed by 90 min of ad libitum feeding in the re-fed females (RF). In addition, food-restricted (FR) females had significantly greater GnRH content in the median eminence than either the AL or RF females. After GnRH was administered, the majority of females in all food conditions ovulated, yet the FR females had significantly fewer corpora lutea than either the AL or RF animals. These data show that food restriction impairs HPG axis function in female musk shrews, and that some of these impairments can be rapidly reversed by acute re-feeding.

Effects of oxytocin on the IGF-axis and some gastrointestinal hormones in ad libitum fed and food-restricted female rats.

The aims of this study were to investigate if administration of oxytocin to ad libitum fed and food-restricted female rats affects weight gain, body fatness, the IGF-axis, and some vagally mediated gastrointestinal hormones, such as gastrin, cholecystokinin (CCK) and somatostatin. Ad libitum fed and food-restricted (receiving 70% of the food intake of the ad libitum fed group) female rats were injected subcutaneously, once a day, for 10 days, with saline (control) or oxytocin (1 mg kg-1 bodyweight). The animals were killed 5 days after the last injection. Oxytocin-treated food-restricted females had more body fat and lower plasma levels of IGF-I, IGFBP-1 and IGFBP-3 compared with saline-treated counterparts. Oxytocin-treated ad libitum fed rats also had lower plasma levels of IGFBP-1 but contained less body fat, compared with saline-treated counterparts. There was no effect of oxytocin treatment on body weight or weight gain in either of the feeding groups. Except for gastrin, which was lower, there was no effect of oxytocin on the gastrointestinal hormones studied. The results indicate that oxytocin treatment influences fat deposition and the IGF-axis in female rats, but that the results are dependent on the nutritional status of the animal.

Changes in neuropeptide Y immunoreactivity in the arcuate nucleus during and after food restriction in lactating rats

Previous studies have demonstrated that food restriction during lactation extends the length of lactational infertility in rats. In order to determine whether Neuropeptide Y (NPY) plays a role in the increased length of lactational infertility seen in food-restricted rats, NPY immunoreactivity in the arcuate nucleus of lactating rats that were ad lib fed or food restricted from Day 8 to 14 postpartum was compared. Food-restricted rats showed higher numbers of NPY-stained cells at the end of the food-restriction period (Day 15 postpartum) than did ad lib-fed rats at the same stage of lactation. This difference persisted until Day 25 postpartum although all animals were fed ad libitum from Day 15 onwards. Switching litters between ad lib-fed and food-restricted females from Day 15 until Day 20 postpartum did not eliminate the difference in NPY immunoreactivity between the two diet conditions. Given that food restriction during lactation leads to a prolonged suppression of LH release that also persists after refeeding and is not affected by the nutritional status of the litter, these data are consistent with a role for NPY in the prolonged suppression of reproductive function seen in food restricted lactating rats.

Female Sexual Behavior Is Inhibited by Short- and Long-term Food Restriction

Gill, C. J. and E. F. Rissman. Female sexual behavior is inhibited by short- and long-term food restriction. Physiol Behav 61(3) 387–394, 1997.—In female musk shrews, sexual receptivity is not restricted to the periovulatory period. Several copulatory bouts that occur over a number of days are required to induce the first ovulation. We tested the hypothesis that food restriction would have a minimal impact on female musk shrew sexual behavior because mating behavior may be uncoupled from ovulation in this species. Three testing conditions were used. In the first study, food-restricted females were maintained at their weaning day weight for 17 days. Food restriction resulted in a significant reduction in the number of females that allowed males to mount, intromit, or ejaculate compared with ad lib-fed controls. In the second experiment, sexually experienced females that were food-restricted for 2 weeks also displayed reduced sexual behavior compared to that in ad lib-fed controls. In the last study, we examined the effects of short-term food fluctuations on sexual behavior. Females food-restricted for 48 h showed reduced mating behavior compared to that in ad lib-fed controls. This was reversed after 24 h of refeeding. These studies show that, even under conditions where copulation does not lead to pregnancy, small reductions in food availability can inhibit female sexual behavior.

Suppression of LH secretion in food-restricted lactating females: effects of ovariectomy and bromocryptine treatment.

It has been shown that restricting food in lactating rats for the first 2 weeks postpartum at a level of 60% of the ad-libitum daily ration increases the length of lactational dioestrus by about 7 days but little is known about correlated changes in hormone levels. In the first experiment we report changes in LH, prolactin (PRL) and ACTH secretion in food-restricted and ad-libitum fed lactating rats at various stages of lactation. Our results demonstrate that food restriction during the first 2 weeks of lactation did not affect PRL or ACTH secretion, but decreased plasma LH levels despite comparable GnRH receptor density between food-restricted and ad-libitum fed females. In the second experiments we investigated a possible causal relationship between the increased secretion of progesterone seen in food-restricted females and the suppression of plasma LH levels, by determining the effects of bromocryptine treatment and ovariectomy on LH secretion in both ad-libitum fed and food-restricted lactating females. LH suppression in food-restricted lactating females was not affected by ovariectomy or bromocryptine treatment, although the latter treatment significantly increased GnRH receptor number. These data suggest that factors other than ovarian steroids, PRL or increased adrenocortical activity modulate LH secretion and the length of lactational dioestrus in food-restricted lactating females.

Survival, body weight, and spontaneous neoplasms in ad Libitum-fed and food-restricted Fischer-344 rats.

Ad libitum-fed (AL) and food-restricted (FR) Fischer-344 male and female rats were monitored for survival, body weight, and spontaneous neoplasms. Mean and maximal lifespans for each group were inversely related to mean body weights. AL males were the shortest lived (mean lifespan 101 wk) followed by AL females (118 wk), FR males (125 wk), and FR females (132 wk). Gross and microscopic examinations were performed on 851 rats from cross-sectional and longevity components of the study. In FR groups, the incidence of mammary gland fibroadenomas, testicular interstitial cell tumors, and pituitary neoplasms was decreased while the latency of these neoplasms was increased. In longevity components, most FR groups had a higher incidence of leukemia than AL cohorts, but all FR groups had a higher mean age at death for the rats with leukemia. Higher leukemia rate in the FR groups was thought to be a result of their extended mean lifespan.

Effects of food restriction on the length of lactational diestrus in rats

The effect of food restriction (60% of an ad lib ration) for the first 14 days postpartum on serum progesterone levels and the duration of lactational diestrus was determined in rat dams nursing litters of eight pups. Food restricted dams showed a longer period of lactational diestrus than ad lib fed dams. Food restriction also caused an increase in progesterone levels that was maintained beyond the period of food restriction itself. Treatment with the dopamine agonist bromocryptine mesylate (0.5 mg/day) either from Day 1 or Day 9 postpartum onward induced early termination of lactational diestrus in both ad lib and food restricted dams but the effect was more rapid in the ad lib fed than in the food restricted females. In both cases, however, the effects of bromocryptine administration on milk delivery showed a similar time course providing indirect evidence that prolactin suppression was equivalent under both diet conditions. These data suggest that food restriction during lactation results in increased progesterone levels that most likely result from increased prolactin release. Further, while prolactin suppression in food restricted dams reduces the duration of lactational diestrus, the latency to do so is somewhat longer than that seen in ad lib fed females, suggesting that some other mechanism may also be operating to suppress ovulation in the food restricted female.

Litter Gender Composition, Food Availability, and Maternal Defence of the Young in House Mice (Mus Domesticus)

AbstractLitter gender composition (LGC) of 33 litters of outbred Swiss albino mice was manipulated at birth to obtain 100%-male litters (MM), 50%-male litters (MF) and 100%-female litters (FF). Litter size was 10 in all cases. Litter defence by their respective dams (5-min exposure to an unfamiliar adult male) was scored on postpartum day 7. The influence of litter gender composition on the female's litter defence was tested, with identical procedure, under conditions of restricted feeding. In this case, dams were fed from postpartum days 1-7 with 80% of their normal daily requirement. Under both ad lib. and restricted feeding body weight of mothers and their litters was assessed daily. Under ad lib. feeding, dams rearing MM litters showed higher scores of Total Attacking Time than both MF and FF dams and higher frequency of Attacks and Tail Rattling episodes than MF dams. Food-restricted females showed a sharp decline in body weight and their litters a slower gain in weight than control animals. LGC did not affect mother and litter weight changes in both conditions but MM females tended to cannibalize more pups on days 6-7 than MF and FF females. Food-restricted MM and MF dams showed, respectively, lower Total Attacking Time and higher number of Attacks and Tail Rattling episodes than their own Control groups. These results show that, under ad lib. feeding, LGC affects significantly female mouse litter defence. Some possible underlying mechanisms are discussed. These results support only partly the TRIVERS-WILLARD'S hypothesis (1973) about sex-biased investment in the offspring since, even though mouse dams under ad lib. feeding defended more vigorously all-male litters, as predicted by the model, among food-restricted animals no clear shift toward a prevalent defence of female-skewed litters appeared.

Short-term hormonal responses to food intake in peripubertal female rats

These studies focused on the phenomenon of "catch-up" pubertal development. Circulating levels of several hormones were characterized in 8-wk-old female rats whose growth and reproductive development had been blocked before puberty by restricting their food intake. Some of these females were fed ad libitum for 24 h to initiate rapid pubertal development. Blood levels of luteinizing hormone (LH) and growth hormone (GH) were suppressed by food restriction and then partially restored to adult diestrus levels by 24 h of ad libitum feeding. Prolactin titers were also suppressed by food restriction but not significantly elevated by 24 h of ad libitum feeding. Circulating levels of follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) were unaffected by either treatment. It is concluded that GH could play an active supplementary role to LH in eliciting catch-up pubertal development but that FSH and TSH could play only passive roles at best. The role of prolactin remains uncertain. On a finer time scale, when food-restricted females were examined in relation to the time of day at which they were fed, most showed high-amplitude LH pulses 2-4 h after eating but rarely at any other time. Thus under some conditions LH secretion can be modulated by food intake on an almost hour-by-hour basis. Overall, blood levels of corticosterone were generally but not always inversely correlated with the frequency of LH pulsing in these experiments. Finally, the present results argue against the concept that puberty is dependent on a critical whole body characteristic.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive responses to variation in temperature and food supply by house mice. I. Mating and pregnancy.

The effects of food restriction upon mating and pregnancy of female house mice were studied at a warm (21 degrees C) and a cold (5 degrees C) temperature to examine the hypothesis that the effects of temperature and food availability are not independent. Analyses of the data showed significant interaction between temperature and food availability for virtually all variables measured, supporting the initial hypothesis. Contingency analysis of mating, fertility, and litter survivorship showed that the interaction influenced not only the percentage of females successfully producing litters, but also the timing of abandonment of reproductive effort by those females that did not have surviving litters. The percentage of females who mated was reduced only in food-restricted females under cold conditions. Both low temperature and food restriction reduced the percentage of mated females that became pregnant. Food-restricted females under cold conditions who did become pregnant tended to kill their litters at birth. The net effect was an interaction between temperature and food restriction that resulted in females reducing or abandoning reproductive effort at progressively earlier stages of the reproductive cycle. The interaction between temperature and food restriction was further displayed in the growth curves of pregnant females, with the reduction of growth by food restriction being greater in the cold.

Alterations in Hepatic Microsomal Mixed-Function Oxidase System during Different Levels of Food Restriction in Adult Male and Female Rats

Wistar strain adult male and female rats were given 25, 50 and 75% less food than an ad libitum-fed group of rats for 45 d and the effects of food restriction on hepatic drug metabolizing enzymes, microsomal electron transport components, NADPH-dependent lipid peroxidation and glutathione-S-transferase activities were studied. Compared to ad libitum-fed controls, the cytochrome P-450 levels were higher in food restricted male rats, while they were lower in food restricted females. The activities of NADPH cytochrome c reductase were lower in food restricted females than in ad libitum-fed controls. The activities of drug metabolizing enzymes, aminopyrine N-demethylase and acetanilide hydroxylase were higher in food restricted males, whereas in food restricted females these activities were lower than in respective groups fed ad libitum. Microsomal, NADPH-dependent lipid peroxidation was higher in 25 and 50% food restricted females while in 50 and 75% food restricted males it was lower than in ad libitum controls of the same sex. The cytosolic glutathione-S-transferase activities were lower in food restricted rats of both the sexes than in the same sexed controls. Another group of male and female rats were given 75% less food than the ad libitum-fed rats and refed for 3 d prior to killing. Here also, the effects of restriction were different between sexes. It is concluded that hepatic microsomal mixed-function oxidase system (MFOS) is altered due to feed restriction and food restriction followed by refeeding, in a sex-related manner.

Loss of Tissues in Female Rats Subjected to Food Restriction during Lactation or during Both Gestation and Lactation

The effects of food restriction (50% of ad libitum-fed controls) on maternal tissues during lactation (LR) or during both gestation and lactation (GLR) were examined in rats. Skeletal muscle protein, RNA and fiber diameter were reduced in response to the LR and GLR treatments, but muscle DNA and fiber number were unchanged. Mean body weights of the pregnant (GLR) and nonpregnant female rats were not significantly different after the first 3 wk of food restriction (after delivery in pregnant GLR rats). Compared to the controls, pups of the GLR females had a significantly smaller mean birth weight. The LR females lost weight and catabolized fat pads, organs, and skeletal muscles while nonlactating females gained weight when given a similar amount of food. These results indicated that the demands of gestation did not significantly add to the loss of maternal body weight due to the restriction of food intake. However, the demands of lactation caused the food-restricted females to catabolize significant amounts of maternal tissues.