Effects of maternal leptin treatment during lactation on the body weight and leptin resistance of adult offspring

We investigate whether leptin treatment to lactating rats affects food intake, body weight and leptin serum concentration and its anorectic effect on their adult offspring. Lactating rats were divided into 2 groups: Lep-single injected with recombinant rat leptin (8 microg/100 g of body weight, daily for the last 3 consecutive days of lactation) and control group (C) that received the same volume of saline. After weaning all pups had free access to the control diet, their body weight and food intake were monitored at each 4 days until 180 days of age, when they were tested for its food intake and response to either leptin (0.5 mg/kg body wt, ip) or saline vehicle. The offspring of the leptin-treated dams gained more weight and had higher food intake from day 37 onward (p<0.05), higher amount of retroperitoneal white adipose tissue (RPWAT) (37%, p<0.05) and higher leptin serum concentration (40%, p<0.05) at 180 days of age compared to control group. The food intake at 2, 4, 6 and 24 h was unaffected after acute injection of leptin in these animals, suggesting resistance to the anorectic effect of leptin. The maternal leptin treatment during lactation makes their adult offspring more susceptible to overweight with resistance to the anorectic effect of leptin.     

Perinatal salt restriction: a new pathway to programming adiposity indices in adult female Wistar rats

Low birth weight has been associated with increased obesity in adulthood. It has been shown that dietary salt restriction during intrauterine life induces low birth weight and insulin resistance in adult Wistar rats. The present study had a two-fold objective: to evaluate the effects that low salt intake during pregnancy and lactation has on the amount and distribution of adipose tissue; and to determine whether the phenotypic changes in fat mass in this model are associated with alterations in the activity of the renin-angiotensin system. Maternal salt restriction was found to reduce birth weight in male and female offspring. In adulthood, the female offspring of dams fed the low-salt diet presented higher adiposity indices than those seen in the offspring of dams fed a normal-salt diet. This was attributed to the fact that adipose tissue mass (retroperitoneal but not gonadal, mesenteric or inguinal) was greater in those rats than in the offspring of dams fed a normal diet. The adult offspring of dams fed the low-salt diet, compared to those dams fed a normal-salt diet, presented the following: plasma leptin levels higher in males and lower in females; plasma renin activity higher in males but not in females; and no differences in body weight, mean arterial blood pressure or serum angiotensin-converting enzyme activity. Therefore, low salt intake during pregnancy might lead to the programming of obesity in adult female offspring.     

Postnatal deficiency of essential fatty acids in mice results in resistance to diet-induced obesity and low plasma insulin during adulthood

Our objective was to investigate the long-term metabolic effects of postnatal essential fatty acid deficiency (EFAD). Mouse dams were fed an EFAD diet or an isoenergetic control diet 4 days before delivery and throughout lactation. The pups were weaned to standard diet (STD) and were later subdivided into two groups: receiving high fat diet (HFD) or STD. Body composition, energy expenditure, food intake and leptin levels were analyzed in adult offspring. Blood glucose and plasma insulin concentrations were measured before and during a glucose tolerance test. EFAD offspring fed STD were leaner with lower plasma leptin and insulin concentrations compared to controls. EFAD offspring fed HFD were resistant to diet-induced obesity, had higher energy expenditure and lower levels of plasma leptin and insulin compared to controls. These results indicate that the fatty acid composition during lactation is important for body composition and glucose tolerance in the adult offspring.     

Excess of Methyl Donor in the Perinatal Period Reduces Postnatal Leptin Secretion in Rat and Interacts with the Effect of Protein Content in Diet

Methionine, folic acid, betaine and choline interact in the one-carbon metabolism which provides methyl groups for methylation reactions. An optimal intake of these nutrients during pregnancy is required for successful completion of fetal development and evidence is growing that they could be involved in metabolic long-term programming. However, the biological pathways involved in the action of these nutrients are still poorly known. This study investigated the interaction between methyl donors and protein content in maternal diet during the preconceptual, pregnancy and lactation periods and the consequences on the rat offspring in the short and long term. Methyl donor supplementation reduced leptin secretion in offspring, whereas insulin levels were mostly affected by protein restriction. The joint effect of protein restriction and methyl donor excess strongly impaired postnatal growth in both gender and long term weight gain in male offspring only, without affecting food intake. In addition, rats born from protein restricted and methyl donor supplemented dams gained less weight when fed a hypercaloric diet. Methylation of the leptin gene promoter in adipose tissue was increased in methyl donor supplemented groups but not affected by protein restriction only. These results suggest that maternal methyl donor supplementation may influence energy homeostasis in a gender-dependent manner, without affecting food intake. Moreover, we showed that macronutrients and micronutrients in maternal diet interact to influence the programming of the offspring.     

Prolactin inhibition in lactating rats changes leptin transfer through the milk.

Malnutrition during lactation reduces milk production and changes pup's leptin serum levels. To test prolactin role in this nutritional state, we evaluated whether prolactin suppression during lactation changes serum leptin in dams, its transfer through the milk, and pup's serum leptin. Lactating rats were treated with bromocryptine (1 mg/twice a day, s.c.) or saline three days before sacrifice (days 2-4 or days 19-21). Food intake and body weight were measured until sacrifice (4th and 21st day). Serum prolactin and leptin were determined by radioimmunoassay. Bromocryptine injected dams had lower serum prolactin and milk production as expected. The mothers presented lower food ingestion (day 21: -25%), lower body weight (day 4: -12%; day 21: -10%), higher serum leptin (day 4: +68%), lower milk leptin on the 4th day (11 times) and higher (8 times) on the 21st day. The offspring of bromocryptine-treated mothers presented lower body weight in both periods of lactation and lower serum leptin on the 4th day (-40%) and higher on the 21st day (+37%) of lactation. We suggest that prolactin, through its effect on leptin secretion into the milk, may play an important role in signalizing maternal nutritional status to the pups.     

Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers

Absence of leptin is known to disrupt the development of energy balance regulatory mechanisms. We investigated whether administration of leptin to normally nourished rats affects energy balance in their offspring. Leptin (2 mg.kg(-1).day(-1)) was administered from day 14 of pregnancy and throughout lactation. Male and female offspring were fed either on chow or on high-fat diets that elicited similar levels of obesity in the sexes from 6 wk to 15 mo of age. Treatment of the dams with leptin prevented diet-induced increases in the rate of weight gain, retroperitoneal fat pad weight, area under the intraperitoneal glucose tolerance curve, and fasting plasma insulin concentration in female offspring. In the male offspring, the diet-induced increase in weight gain was prevented and increased fat pad weight was reduced. Energy intake per rat was higher in response to the obesogenic diet in male offspring of saline-treated but not leptin-treated dams. A similar trend was seen in 3-mo-old female offspring. Energy expenditure at 3 mo of age was higher for a given body weight in female offspring of leptin-treated compared with saline-treated dams when these animals were fed on the obesogenic diet. A similar trend was seen for male rats fed on the obesogenic diet. Thus leptin levels during pregnancy and lactation can affect the development of energy balance regulatory systems in their offspring.     

Maternal melatonin influences rates of somatic and reproductive organs postnatal development of male rat offspring

Female rat dams, housed in 12L:12D photoperiod, were pinealectomized or injected daily 1(1/2) h before onset of darkness with 250 mg melatonin/100 g BW., during pregnancy; control and pinealectomized dams received a placebo. Somatic, reproductive organs and gonadotropins levels luteinizing hormone (LH) and follicle stimulating hormone (FSH) of male offspring were examined at the following phases of their sexual development: neonate, infantile, juvenile or prepubertal and pubertal periods. Pinealectomy of the mother produced an altered developmental pattern in the offspring (PIN-X offspring). During the infantile period when pups are lacking maternal melatonin and their own melatonin rhythm is not yet established, a delayed growth of body and testis weights was observed. After the second week of life, from 15 to 25 days of age, coinciding with the initiation of the melatonin rhythm, a speed-up growth of body and testes was observed, followed by a delayed growth from 25 to 30 days, in the juvenile period; this also coinciding with reduced LH levels observed at 30 days of age. Indeed, in PIN-X offspring significantly greater growth rate was observed during the pubertal period than in control offspring, which could be due to the increase in LH secretion up to normal values observed in the PIN-X offspring. Seminal vesicles of the PIN-X offspring also showed delayed growth, which was overcome at the pubertal period. Melatonin (MEL) treatment during pregnancy produced minor alterations in postnatal development of the reproductive tract. Only increased pituitary gland weight was observed at 15 and decreased at 25 days of age. At 25 days of age, MEL offspring reached the highest LH values, and at 30 days of age, PIN-X offspring still show low values. Which suggests that other factors than the endocrine activity of the gland are affecting the somatic growth of the pituitary gland. Seminal vesicles weight was delayed at 25 days of age in the MEL offspring. These results indicate that maternal melatonin is necessary for a normal somatic growth and postnatal development of reproductive organs of the offspring.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

Maternal tobacco smoke exposure during lactation inhibits catecholamine production by adrenal medullae in adult rat offspring

Previously, we have shown that maternal smoke exposure during lactation, even when pups are not exposed, affects biochemical profiles in the offspring at weaning, eliciting lower body adiposity, hyperinsulinemia, hypocorticosteronemia and lower adrenal catecholamine content. However, the future impact of tobacco exposure is still unknown. As postnatal nicotine exposure causes short- and long-term effects on pups' biochemistry and endocrine profiles, we have now evaluated some endocrine and metabolic parameters of the adult offspring whose mothers were tobacco exposed during lactation. For this, from day 3 to 21 of lactation, rat dams were divided in: 1) SE group, cigarette smoke-exposed (1.7 mg nicotine/cigarettes for 1 h, 4 times/day, daily), without their pups, and 2) C group, exposed to air, in the same conditions. Offspring were killed at 180-days-old. Body weight and food intake were evaluated. Blood, white adipose tissue, adrenal, and liver were collected. All significant data were p<0.05. The adult SE offspring showed no change in body weight, cumulative food intake, serum hormone profile, serum lipid profile, or triglycerides content in liver. However, in adrenal gland, adult SE offspring showed lower catecholamine content ( - 50%) and lower tyrosine hydroxylase protein expression ( - 56%). Despite the hormonal alterations during lactation, tobacco smoke exposure through breast milk only programmed the adrenal medullary function at adulthood and this dysfunction can have consequence on stress response. Thus, an environment free of smoke during lactation period is essential to improve health outcomes in adult offspring.     

Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats

The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.     

The food intake of rats during pregnancy and lactation

Quantities of food required by Sprague-Dawley rats during gestation and lactation and in the post-lactation period were examined. Rats allowed to eat ad libitum during pregnancy consumed quantities of food only slightly greater than the amount reported to be the average intake of pregnant Sprague-Dawley rats (20 g/day). Rats delivered their pups on day 22 or day 23 of the gestation period, but regardless of the day of delivery, the food intake of each rat decreased on day 21 of pregnancy and then decreased a second time on the day of parturition. During lactation, food consumption of the rats soon exceeded the amount reported as the average intake of lactating rats (30-35 g/day). Food intake was found to escalate from 12.2 +/- 3.1 g/rat on day 0 of lactation, the lowest intake in the study, to 94.4 +/- 23.7 g on day 21 of lactation. However, in the latter part of the lactation period, the intake represented the combined food intake of dams and pups. Eight days in the post-lactation period were required for food intake of dams to return to a level near that recorded at the beginning of pregnancy.     

Pre- and Postnatal Nutritional Histories Influence Reproductive Maturation and Ovarian Function in the Rat

Background

While prepubertal nutritional influences appear to play a role in sexual maturation, there is a need to clarify the potential contributions of maternal and childhood influences in setting the tempo of reproductive maturation. In the present study we employed an established model of nutritional programming to evaluate the relative influences of prenatal and postnatal nutrition on growth and ovarian function in female offspring.

Methods

Pregnant Wistar rats were fed either a calorie-restricted diet, a high fat diet, or a control diet during pregnancy and/or lactation. Offspring then were fed either a control or a high fat diet from the time of weaning to adulthood. Pubertal age was monitored and blood samples collected in adulthood for endocrine analyses.

Results

We report that in the female rat, pubertal timing and subsequent ovarian function is influenced by the animal''s nutritional status in utero, with both maternal caloric restriction and maternal high fat nutrition resulting in early pubertal onset. Depending on the offspring''s nutritional history during the prenatal and lactational periods, subsequent nutrition and body weight gain did not further influence offspring reproductive tempo, which was dominated by the effect of prenatal nutrition. Whereas maternal calorie restriction leads to early pubertal onset, it also leads to a reduction in adult progesterone levels later in life. In contrast, we found that maternal high fat feeding which also induces early maturation in offspring was associated with elevated progesterone concentrations.

Conclusions

These observations are suggestive of two distinct developmental pathways leading to the acceleration of pubertal timing but with different consequences for ovarian function. We suggest different adaptive explanations for these pathways and for their relationship to altered metabolic homeostasis.     

Maternal obesity at conception programs obesity in the offspring

Risk of obesity in adult life is subject to programming during gestation. To examine whether in utero exposure to maternal obesity increases the risk of obesity in offspring, we developed an overfeeding-based model of maternal obesity in rats utilizing intragastric feeding of diets via total enteral nutrition. Feeding liquid diets to adult female rats at 220 kcal/kg(3/4) per day (15% excess calories/day) compared with 187 kcal/kg(3/4) per day for 3 wk caused substantial increase in body weight gain, adiposity, serum insulin, leptin, and insulin resistance. Lean or obese female rats were mated with ad libitum AIN-93G-fed male rats. Exposure to obesity was ensured to be limited only to the maternal in utero environment by cross-fostering pups to lean dams having ad libitum access to AIN-93G diets throughout lactation. Numbers of pups, birth weight, and size were not affected by maternal obesity. Male offspring from each group were weaned at postnatal day (PND)21 to either AIN-93G diets or high-fat diets (45% fat calories). Body weights of offspring from obese dams did not differ from offspring of lean dams when fed AIN-93G diets through PND130. However, offspring from obese dams gained remarkably greater (P < 0.005) body weight and higher % body fat when fed a high-fat diet. Body composition was assessed by NMR, X-ray computerized tomography, and weights of adipose tissues. Adipose histomorphometry, insulin sensitivity, and food intake were also assessed in the offspring. Our data suggest that maternal obesity at conception leads to fetal programming of offspring, which could result in obesity in later life.     

黑线仓鼠断乳后能量代谢和脂肪累积的适应性调节

小型哺乳动物能量代谢和脂肪累积的适应性调节是其应对自然环境变化的主要能量学策略,但在不同的生活史阶段,脂肪组织适应性调节的特征和能量机理尚不清楚。为探讨不同繁殖阶段能量代谢和脂肪累积的变化及其内分泌机理,本文测定了黑线仓鼠哺乳期和断乳后摄食量、脂肪重量,以及血清瘦素水平、下丘脑瘦素受体（Ob-Rb）和相关神经肽的基因表达。结果显示,哺乳高峰期黑线仓鼠的脂肪重量几乎降低至零,断乳后显著增加;与非繁殖对照组相比,皮下脂肪、肾周脂肪与腹腔脂肪重量分别增长了1.5倍、37.1倍和1.9倍。断乳后摄食量、血清瘦素水平显著高于非繁殖对照组,Ob-Rb基因表达显著下调,而促食与抑食神经肽的基因表达均未发生显著变化。哺育不同胎仔数的黑线仓鼠在断乳后能量摄入、静止代谢率、身体组分未出现显著差异。研究表明,在不同的繁殖阶段脂肪累积呈现显 著的适应性调节,瘦素抵抗是断乳后脂肪累积补偿性增长的重要内分泌机制之一。这对迅速恢复脂肪累积,以应对将来的能量需求增加或者食物资源短缺的环境,进而提高自身的适合度具有重要意义。     

Leptin serum concentration,food intake and body weight in rats whose mothers were exposed to malnutrition during lactation

We had shown that adult animals, whose mothers were submitted to protein or energy restriction during lactation, differ from controls in their body weight and thyroid function. The aim of this study was to evaluate, from birth through six months of age, leptin serum concentration, body weight and food intake in animals whose mothers received protein or energy restricted-diet during lactation as follows: control (C)-23% protein; protein-restricted (PR)-8% protein; energy-restricted (ER)-23% protein, in restricted quantity, according to the mean ingestion of the PR group. After weaning (day 21) all pups had free access the control diet. Body weight of pups from PR mothers were always lower than those from controls (p < 0.05), while body weight of pups from ER mothers surpassed that of the C group significantly at 140 days of age. The food intake was lower in both offspring from PR and ER mothers, normalizing on the 32th day in pups from ER mothers and on the 52th day in pups from PR mothers. Leptin serum concentration in both offspring from PR and ER mothers were significantly decreased on the 12th day (p < 0.05) and increased on the 21st day (p < 0.05) compared to control. After weaning there was no differences among the groups. It is possible that changes in leptin concentration during lactation in the offspring of malnourished groups could permanently modify the setpoint for body weight control.     

Effect of mother’s physical condition during pregnancy and lactation on postnatal growth and reproductive success of offspring in water vole <Emphasis Type="Italic">Arvicola terrestris</Emphasis>

Postnatal growth, life span, and probability of reproduction in the adult state depended on the mother’s physical condition during pregnancy and lactation in water vole. The white fat weight in the female abdominal cavity was shown to significantly increase in pregnancy and to decrease in late lactation. As an indicators for nutritional state of females, their body weight difference after parturition (or in late lactation) and expected from the regression equation relating individual body weight at the beginning and the end of each reproductive stage were used (physical condition indexes in pregnancy or lactation). The correlation of the physical condition index in pregnancy with the storage fat weight was 0.67. The metabolic resources of the mother’s body proved to favor faster offspring development. The female offspring weight at the age of 3 and 10 weeks as well as adult ones positively correlated with the mother’s nutritional state in pregnancy, while the male offspring weight demonstrated a similar correlation at the age of 3 and 6 weeks. Increased negative energy balance during lactation proved to decrease the offspring weight in both sexes after separation from mother and at the age of 6 weeks. High nutritional state of mother in pregnancy favored both the probability of reproduction and life span of female offspring. The reproduction of male offspring did not depend on the mother’s physical condition. The life span peaked in male offspring of mothers in a nutritional state below average in pregnancy and above average in lactation. Thus, the physical condition of the mother’s body is an important sex-dependent factor of phenotypic variation in the offspring body weight, reproductive competence, and life span.     

Effect of mother's physical condition during pregnancy and lactation on postnatal growth and reproductive success of offspring in water vole Arvicola terrestris L

Postnatal growth, life span, and probability of reproduction in the adult state depended on the mother's physical condition during pregnancy and lactation in water vole. The white fat weight in the female abdominal cavity was shown to significantly increase in pregnancy and to decrease in late lactation. As an indicators for nutritional state of females, their body weight difference after parturition (or in late lactation) and expected from the regression equation relating individual body weight at the beginning and the end of each reproductive stage were used (physical condition indexes in pregnancy or lactation). The correlation of the physical condition index in pregnancy with the storage fat weight was 0.67. The metabolic resources of the mother's body proved to favor faster offspring development. The female offspring weight at the age of 3 and 10 weeks as well as adult ones positively correlated with the mother's nutritional state in pregnancy, while the male offspring weight demonstrated a similar correlation at the age of 3 and 6 weeks. Increased negative energy balance during lactation proved to decrease the offspring weight in both sexes after separation from mother and at the age of 6 weeks. High nutritional state of mother in pregnancy favored both the probability of reproduction and life span of female offspring. The reproduction of male offspring did not depend on the mother's physical condition. The life span peaked in male offspring of mothers in a nutritional state below average in pregnancy and above average in lactation. Thus, the physical condition of the mother's body is an important sex-dependent factor of phenotypic variation in the offspring body weight, reproductive competence, and life span.     

Different physiological roles of serum leptin in the regulation of energy intake and thermogenesis between pregnancy and lactation in primiparous Brandt's voles (Lasiopodomys brandtii)

Reproduction, especially lactation, is associated with major metabolic adaptive changes. In this study, we investigated the metabolic changes and the roles of leptin during different periods of reproduction in primiparous Brandt's voles (Lasiopodomys brandtii). Energy intake, thermogenic capacity and serum leptin levels were examined in non-reproductive, mid pregnant, late pregnant, early lactating and peak lactating voles. Voles increased body mass by nearly 70% during late pregnancy compared to the non-breeding controls. The increase in body mass was mainly due to the increase in body fat mass which increased by 56%, and the growth of the reproductive tissues and digestive organs. Lactating voles decreased body fat by nearly 27% at peak lactation compared to the controls, and 53% compared to late pregnant voles. At the same time they increased food intake significantly. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) decreased significantly at peak lactation. Serum leptin increased significantly in the mid pregnancy, at a time when there was no increase in body fat, and remained at this high level in late pregnancy. Leptin levels decreased after parturition and reached a nadir at peak lactation. Serum leptin was negatively correlated with energy intake during lactation, but not during pregnancy. These data suggest that Brandt's voles adjust energy intake, thermogenic capacity and body reserves to match the high energy demands for reproduction. Hyperleptinemia, without decreased energy intake suggests a state of leptin resistance during pregnancy, and hypoleptinemia during lactation might act as a signal to stimulate energy intake.     

Selective Leptin Insensitivity and Alterations in Female-Reproductive Patterns Linked to Hyperleptinemia during Infancy

The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK₁ deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health.