Postnatal Overfeeding Causes Early Shifts in Gene Expression in the Heart and Long-Term Alterations in Cardiometabolic and Oxidative Parameters

Background

Postnatal overfeeding (OF) in rodents induces a permanent moderate increase in body weight in adulthood. However, the repercussions of postnatal OF on cardiac gene expression, cardiac metabolism and nitro-oxidative stress are less well known.

Methodology/Principal Findings

Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet. The cardiac gene expression profile was determined at weaning and cardiac metabolism and oxidative stress were assessed at 7 months. The cardiac expression of several genes, including members of the extracellular matrix and apelin pathway, was modified in juvenile OF mice. In adult mice, OF led to an increase in body weight (+30%) and to significant increases in plasma cholesterol, insulin and leptin levels. Myocardial oxidative stress, SOD and catalase activity and mRNA expression were increased in OF mice. In vivo, diastolic and systolic blood pressures were significantly higher and LV shortening and ejection fraction were decreased in OF mice. Ex vivo, after 30 min of ischemia, hearts isolated from OF mice showed lower functional recovery and larger infarct size (31% vs. 54%, p<0.05). Increases in collagen deposition and expression/activity of matrix-metalloproteinase-2 were observed in adult OF mouse hearts. Moreover, an increase in the expression of SOCS-3 and a decrease in STAT-3 phosphorylation were observed in ventricular tissues from OF mice.

Conclusions/Significance

Our study emphasizes that over-nutrition during the immediate postnatal period in mice leads to early changes in cardiac gene expression, which may permanently modify the heart’s structural organization and metabolism and could contribute to a greater susceptibility to myocardial ischemia-reperfusion injury.     

Mitochondrial impairment following neonatal overfeeding: A comparison between normal and ischemic-reperfused hearts

Overweight and obesity are established factors underpin several metabolic impairments, including the cardiovascular. Although the diversity of factors involved in overweight/obesity-induced cardiovascular diseases, mitochondria has been highlighted due to its role in cardiac metabolism. As obesity can be originated in early postnatal life, the current study evaluates the effects of neonatal overfeeding on the cardiac mitochondrial bioenergetics and oxidative balance in rats that underwent an ischemia-reperfusion insult. Seventy-two hours after delivery, Wistar rat litters were randomly assigned into the control (C; nine pups per mother) and the Overfed (OF; three pups per mother) groups throughout the lactation period. At weaning, male offspring were fed with laboratory chow ad libitum until sacrifice at 30 and 60 days of life. Mitochondrial heart bioenergetics and oxidative balance showed to be deeply affected by neonatal overfeeding at both ages. Interestingly, after ischemia-reperfusion insult I/R (Langendorff or mineral oil incubation), most parameters evaluated in OF animals were not influenced by additional ischemic-reperfusion injury. Our findings demonstrated that suckling overfeeding deregulates cardiac mitochondrial alike to ischemia-reperfusion insult by disengaging electrical mitochondrial coupling and potentiate oxidative stress, wherein the neonatal overfeeding shows to be so detrimental as I/R. Our findings support the concept that nutritional insults in the critical development periods increase the risk for cardiovascular disease and mitochondria impairments throughout life while oxidative damage change between molecular targets.     

Oxidative stress programming in a rat model of postnatal early overnutrition — role of insulin resistance

Postnatal early overfeeding (EO) is related to later development of overweight and other metabolic disorders. As oxidative stress is implicated in most human diseases, as obesity and diabetes, we decided to study some parameters related to oxidative stress and insulin signaling in liver from EO animals in adult life. To induce EO, litter size was reduced to three pups per litter (SL: small litter) and groups with normal litter size (NL:10 pups per litter) were used as control. After weaning, rats had free access to standard diet and water. Body weight and food intake were monitored daily and offspring were killed at 180 days-old. Significant differences had P<.05 or less. As expected, SL rats had hyperphagia, higher body weight and higher visceral fat mass at weaning and adulthood. In liver, postnatal EO programmed for lower catalase (? 42%), superoxide dismutase (? 45%) and glutathione peroxidase (? 65%) activities. The evaluation of liver injury in adult SL group showed lower nitrite content (? 10%), higher liver and plasma malondialdehyde content (+ 25% and 1.1-fold increase, respectively). No changes of total protein bound carbonyl or Cu/Zn superoxide dismutase protein expression in liver were detected between the groups. Regarding insulin signaling pathway in liver, SL offspring showed lower IRβ (? 66%), IRS1 (? 50%), phospho-IRS1 (? 73%), PI3-K (? 30%) and Akt1 (? 58%). Indeed, morphological analysis showed that SL rats presented focal areas of inflammatory cell infiltrate and lipid drops in their cytoplasm characterizing a microsteatosis. Thus, we evidenced that postnatal EO can program the oxidative stress in liver, maybe contributing for impairment of the insulin signaling.     

Resveratrol attenuates oxidative stress and prevents steatosis and hypertension in obese rats programmed by early weaning

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) — dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control — dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) — resveratrol (30 mg/kg/day); EW+vehicle (EW) — rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and ?13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, ?58%, ?31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.     

Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats

Postnatal early overnutrition (EO) is a risk factor for future obesity and metabolic disorders. Rats raised in small litters (SLs) develop overweight, hyperphagia, hyperleptinemia, hyperinsulinemia and hypertension when adults. As obesity is related to hyperleptinemia, leptin resistance and metabolic syndrome, we aimed to investigate body composition, plasma hormone levels, glucose tolerance and the leptin signaling pathway in hypothalamus from early overfed animals at weaning and adulthood. To induce postnatal EO, we reduced litter size to three pups/litter (SL), and the groups with normal litter size (10 pups/litter) were used as control. Rats had free access to standard diet and water postweaning. Body weight and food intake were monitored daily, and offspring were killed at 21 (weaning) and 180 days old (adulthood). Postnatal EO group had higher body weight and total and visceral fat mass at both periods. Lean mass and serum high-density lipoprotein cholesterol (HDL-C) were higher at 21 days and lower at 180 days. Small litter rats presented higher levels of globulins at both periods, while albumin levels were higher at weaning and lower at adulthood. There was higher leptin, insulin and glucose serum concentrations at 21 days old, while no glucose intolerance was observed in adulthood. Leptin signaling pathway was unaffected at weaning. However, postnatal EO induced lower JAK2 and p-STAT3, and higher SOCS3 expression in adult animals, indicating central leptin resistance in adulthood. In conclusion, postnatal EO induces obesity, higher total and visceral fat mass, lower HDL-C and central leptin resistance in adult life.     

Neonatal overnutrition programming impairs cholecystokinin effects in adultmale rats

Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity.     

Hypothalamic ventromedial and arcuate neurons of normal and postnatally overnourished rats differ in their responses to melanin-concentrating hormone

Melanin-concentrating hormone (MCH) is a neuropeptide involved in regulation of food intake and body weight. The study aimed to detect possible differences in responses of hypothalamic ventromedial and arcuate neurons to MCH, depending on the short-term nutritional state (fed versus food-deprived) and on the long-term state in overweight rats due to early postnatal overnutrition. The effect of MCH on a single-unit activity was studied in brain slices of normal and overweight rats. The latter (n=16) were raised till weaning in small litters (SL) of 3 pups compared to 10 pups in control litters (CL) and gained significantly greater body mass. Whereas MCH in effective concentrations in the pico- to nanomolar range could increase or suppress the activity of ventromedial or arcuate neurons studied in male normal fed or food-deprived (24 h) rats, its action became shaped in an unidirectional way in overweight, hyperphagic rats. Medial arcuate neurons (n=25) from hyperphagic rats were predominantly activated by MCH (p<0.05, paired t-test). This effect differed significantly from that induced on neurons (n=27) of control rats. Ventromedial neurons (n=34) of overweight rats were predominantly inhibited. Activation of arcuate neurons may induce feeding in particular through release of neuropeptide Y (NPY). Inhibition of ventromedial neurons may contribute to reduced energy expenditure. The increased expression of one response type to MCH by a neuronal population in overweight, hyperphagic rats might reflect a general mechanism of neurochemical plasticity and also suggest a participation of the peptide in long-term regulation of food intake and body weight in this model of obesity.     

Overfeeding during lactation modulates insulin and leptin signaling cascade in rats' hearts

Insulin has been described as a potential mediator of intrinsic responses to the nutritional state in the heart due to its effects on cardiac metabolism, mainly on glucose transport. It has been demonstrated that leptin can act through some components of the insulin-signaling cascade. We investigated the association between overfeeding during lactation and alterations of insulin and leptin signaling in the heart. In summary, we analyzed a feasible cross-talk between insulin and leptin through the study of some key proteins of their cascades in the heart. In order to study the effect of overfeeding on these cascades, Wistar rats were overfed through litter size reduction to only three pups. At 10 and 21 days of life, key proteins such as insulin receptor, leptin receptor, PI3-kinase, JAK2, STAT3, and GLUT4 were measured by Western blotting. Furthermore, the pups' weight and the plasma levels of insulin, leptin and glucose were determined. Overfed animals were overweight, had high insulin and leptin plasma levels, and displayed an activation of insulin and leptin cascade, leading to an increased translocation of GLUT4. We suggest that overfeeding during lactation probably alters cardiac metabolism, through the activation of a modulated cross-talk between leptin and insulin cascades.     

Preweaning over- and underfeeding alters onset of puberty in the rat without affecting kisspeptin

The perinatal nutritional environment can permanently influence body weight, potentially leading to changes in puberty onset and reproductive function. We hypothesized that perinatal under- or overfeeding would alter puberty onset and influence concentrations of a neuropeptide crucial for successful puberty, kisspeptin. We manipulated Wistar rat litter sizes to derive small (SL), control (CL), and large (LL) litters containing 4, 12, and 20 rat pups respectively. This manipulation results in an overweight phenotype in SL rats and a lean phenotype in LL that persists throughout life. To investigate whether successful puberty onset is affected by neonatal under- or overfeeding, we examined indices of growth and development, including the onset of puberty, as well as the central expression of Kiss1 mRNA in these pups. Male LL rats reached puberty later than those from CL. These males also had reduced plasma testosterone and elevated 17beta-estradiol concentrations at puberty. The age at puberty onset was not affected in SL males despite accelerated growth. In females, puberty onset was not significantly delayed by having a lean phenotype, and steroid hormones were not affected. The age at onset was, however, younger in the SL females. Kiss1 mRNA in the hypothalamus was not affected by neonatal nutrition either at puberty or 7 days later. Our findings show early life underfeeding in males and overfeeding in females significantly affects puberty onset, altering steroid hormone concentrations in males, but this is not related to changes in hypothalamic kisspeptin.     

The effect of overfeeding the young in early postnatal ontogeny on brown fatty tissue

We studied the effects of overfeeding of neonatal Wistar rats on O2 consumption by the interscapular brown adipose tissue and DNA content in the tissue. The overfeeding was induced by reducing the litter size to two to three pups per dam compared with standard litters of five to ten pups. All animals were allowed free access to water and forage and were kept at 24 +/- 1 degrees C. Newborn and 16-day-old rat pups were used in the experiments. The body weight of overfed pups was significantly higher than that of standard fed pups (p < 0.001). There were no differences between groups of 16-day-old rats in the resting metabolic rate. The mass of dried brown adipose tissue relative to the body mass in overfed pups was lower than in the control pups (p < 0.01). O2 consumption in the rats from small litters was 35% higher (p < 0.001). DNA content (mg/g brown adipose tissue) in overfed rats was 35% lower as compared to the control pups (p < 0.001). These results indicate that overfeeding at the preweaning stage of life affects growth, cellularity, and thermogenic function of brown adipose tissue.     

Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring

Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+17%) with hyperleptinemia and hyperinsulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood.     

Overnutrition during lactation leads to impairment in insulin signaling,up-regulation of GLUT1 and increased mitochondrial carbohydrate oxidation in heart of weaned mice

Several studies have demonstrated that overnutrition during early postnatal period can increase the long-term risk of developing obesity and cardiac disorders, yet the short-term effects of postnatal overfeeding in cardiac metabolism remains unknown. The aim of our study was to investigate the cardiac metabolism of weaned mice submitted to overnutrition during lactation, particularly as to mitochondrial function, substrate preference and insulin signaling. Postnatal overfeeding was induced by litter size reduction in mice at postnatal day 3. At 21 days of age (weaning), mice in the overfed group (OG) presented biometric and biochemical parameters of obesity, including increased body weight, visceral fat, liver weight and increased left ventricle weight/tibia length ratio; indicating cardiac hypertrophy, hyperglycemia, hyperinsulinemia and increased liver glycogen content compared to control group. In the heart, we detected impaired insulin signaling, mainly due to decreased IRβ, pTyr-IRS1, PI3K, GLUT4 and pAkt/Akt and increased PTP1B, GLUT1 and pAMPKα/AMPKα content. Activities of lactate dehydrogenase and citrate synthase were increased, accompanied by enhanced carbohydrate oxidation, as observed by high-resolution respirometry. Moreover, OG hearts had lower CPT1, PPARα and increased UCP2 mRNA expression, associated with increased oxidative stress (4-HNE content), BAX/BCL2 ratio and cardiac fibrosis. Ultrastructural analysis of OG hearts demonstrated mild mitochondrial damage without alterations in OXPHOS complexes. In conclusion, overnutrition during early life induces short-term metabolic disturbances, impairment in heart insulin signaling, up-regulates GLUT-1 and switch cardiac fuel preference in juvenile mice.     

Early weaning programs rats to have a dietary preference for fat and palatable foods in adulthood

The objective of this work was to study the effect of early weaning on alimentary preference for the macronutrients protein, carbohydrate and fat in adult rats. Male Wistar rat pups were weaned by separation from the mother at 15 (D15) or 30 (D30) days old. Body weight and food intake were measured every 30 days until pups were 150 days old. At 110 days of age, the alimentary preference was evaluated for 1 h on 3 consecutive days. At 120 days of age, the palatable diet test was conducted during 3 consecutive 24-h periods. Body weight and food intake were not altered, but early weaning in rats induced an alimentary preference to fat and hyperphagia of a palatable diet. In conclusion, early weaning, although did not modify body weight or basal food intake, promoted an increased preference for palatable and fatty foods. This demonstrates that early weaning is not capable of promoting perceptible alterations of alimentary behavior under normal laboratory conditions. However, in the presence of a stimulating factor such as a choice of nutrients or a palatable diet, a possible latent effect on dietary preferences may become apparent. Over the long term, this preference for foods with high caloric density can lead to obesity and metabolic perturbations.     

Developmental changes of glucocorticoid receptors in the rat pancreas

Glucocorticoids are known to play a role in the maturation of the exocrine pancreas. The exact mechanism of glucocorticoid action in pancreatic ontogeny is, however, not clear. The present study characterized and quantitated the binding of [3H]dexamethasone to cytosol fractions from pancreata of rats at various ages. Trunk blood samples from these rats were also checked for levels of free and bound corticosterone. Specific and saturable bindings for dexamethasone were found in pancreatic cytosol fractions from newborn suckling and adult rats. Competition studies showed a preference for steroids with glucocorticoid activity. Specific binding was relatively low in pancreatic cytosol from newly born and 1-day old pups. A significant rise was seen after day 15. Cytosolic binding capacities were greatest from pancreata obtained from pups at weaning (3rd to 5th weeks). Values then declined toward the adult level. Scatchard analysis revealed a single class of binding sites with a dissociation constant (Kd) of 7.3 (+/- 1.1) X 10(-8) M and number of binding sites equalled to 1.29 (+/- 0.18) X 10(-13) mole/mg of cytosolic protein in adult rat pancreas. Pancreata from 25- and 15-day old rats had Kds of 3.4 (+/- 0.8) X 10(-8) M and 2.7 (+/- 0.7) X 10(-8) M with the number of binding sites equal to 1.77 (+/- 0.21) X 10(-13) mole/mg protein and 1.31 (+/- 0.16) X 10(-13) mole/mg protein respectively. Total plasma corticosterone concentration was low before day 10. It rose significantly by day 15, peaked at day 25, and then declined after weaning. About 5-15% of corticosterone during weaning and about 20-30% before and after weaning were in the free form. The peak level of dexamethasone binding corresponded to an increase in the plasma corticosterone level during weaning. This suggests a close relationship between plasma corticosterone levels and pancreatic glucocorticoid receptors. Both may, therefore, play a role in pancreatic development in the rat.     

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.     

Hypothalamic orexigenic peptides are overexpressed in young Long-Evans rats after early life exposure to fat-rich diets

Nutritional factors have a critical influence during prenatal life on the development and regulation of networks involved in body weight and feeding regulation. To establish the influence of the macronutrient type on feeding regulatory mechanisms and more particularly on stimulatory pathways (galanin and orexins), we fed female rats on either a high-carbohydrate (HC), a high-fat (HF), or a well-balanced control diet during gestation and lactation, and measured peptide expression in the hypothalamus and important hormones (leptin, insulin) in their pups at weaning. HF weanlings were 30% lighter than control and HC pups (P<0.001). They were characterized by reduced plasma glucose and insulin levels (P<0.01 or less). Their galanin and orexin systems were upregulated as shown by the significant augmentation of mRNA expression in the paraventricular nucleus and lateral hypothalamus, respectively. Inhibitory peptides like corticotropin-releasing hormone and neurotensin were not affected by this dietary treatment during early life. There was, therefore, a more intense drive to eat in HF pups, perhaps to compensate for the lower body weight at weaning. HF diets during early life had meanwhile some positive consequences: the lower metabolic profile might be beneficial in precluding the development of obesity and metabolic syndrome later in life. This is however valid only if the orexigenic drive is normalized after weaning.     

Measurement of body composition in response to a short period of overfeeding

Background

Obesity and overweight are increasing in prevalence in developed countries as a result of changing dietary habits and a lack of physical activity. The purpose of the present study was to evaluate the changes in body composition during short-term overfeeding using the three-component model, which is composed of fat mass (FM), total body water (TBW), and fat-free dry solids (FFDS).

Methods

Ten healthy men completed 3 days of overfeeding during which they consumed 1,500 kcal/day more energy than consumed in their normal diets. Body composition was evaluated at three time points: the day before and after their normal diets and the day after the 3-day overfeeding diet.

Results

Before and after their normal diets, there were no significant differences in body weight and composition, but after 3 days of overfeeding, body weight, TBW, and FFDS increased 0.7, 0.7, and 0.2 kg, respectively (P <0.0001). There was no significant difference in FM between the normal and overfeeding diets.

Conclusion

This study suggests that TBW gain contributes to weight gain following a short-term overfeeding.     

Doxorubicin induced neuro- and cardiotoxicities in experimental rats: Protection against oxidative damage by Theobroma cacao Stem bark

80 rats, randomly selected, were divided into 3 treatment groups: pre-, co- and post-treatment; consisting of 6 sub-groups each (5 rats per sub-group): baseline, normal saline (2 mL), α-lipoic acid (20 mg/kg body weight), 200 mg/kg, 400 mg/kg or 800 mg/kg body weight Theobroma cacao stem bark aqueous extract (TCAE). All rats except for baseline group were intoxicated with 20 mg/kg body weight doxorubicin (DOX) intraperitoneally. The animals in pre- or post-treatment group received a single dose of DOX (20 mg/kg body weight) intraperitoneally 24 h before or after 7 days’ oral administration with TCAE respectively while those in co-treatment group were co-administered 2.86 mg/kg body weight of DOX with either normal saline, α- lipoic acid or TCAE orally for 7 days. Animals were sacrificed (pre- and post- treatment groups were sacrificed on the ninth day while the co-treatment group sacrificed on the 8th day). Brain and heart tissue samples were harvested for enzyme markers of toxicity, oxidative stress and histopathological examinations. DOX intoxication caused significant decrease in activities of LDH and ACP, and increase in γGT and ALP activities in brain tissues while causing a significant increase in LDH, ACP, γGT activities and decrease in ALP activity in the cardiac tissues. DOX intoxication caused a significant increase in concentrations of H₂O₂ generated, MDA and PC, XO, MPx and NOX activities with concomitant decrease in CAT, SOD, GPx and GST activities, and in concentrations of GSH, AsA and α-Toc in brain and cardiac tissues. Pre-, co- and post-treatment with TCAE at either 200 mg/kg, 400 mg/kg or 800 mg/kg body weight significantly reversed the oxidative damage to the organs induced by DOX-intoxication. The result affirmed that T. cacao stem bark aqueous extract protected against DOX induced oxidative damage in brain and cardiac tissues of experimental rats.     

Involvement of the GHSR in the developmental programming and metabolic disturbances induced by maternal undernutrition

The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)^−/− mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR^−/− pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR^−/− UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.     

Effects of early weaning on the circadian rhythm and behavioral satiety sequence in rats

The objective of this work was to study the effect of early weaning on circadian rhythm and the behavioral satiety sequence in adult rats. Male Wistar rat pups were weaned for separation from the mother at 15 (D15), 21 (D21) and 30 (D30) days old. Body weight and food intake was measured every 30 days until pups were 150 days old. At 90 days of age, the circadian rhythm of food intake was evaluated every 4 h for three days. Behavioral satiety was evaluated at 35 and 100 days of age. This work demonstrated that body weight and food intake were not altered, but the behavioral satiety sequence demonstrated that the D15 group delayed satiety compared with the D30 group at 100 days of age. In the circadian rhythm of the food intake study, early weaning (D15) changed food intake in the intermediary period of the light phase and in the intermediary period of the dark phase. In conclusion, our study showed that early weaning may alter the feeding behavior mainly in relation to satiety and the circadian rhythm of feeding. It is possible that the presence of other environmental stimuli during early weaning can cause hyperphagia and deregulate the mechanisms of homeostasis and body weight control. This study supports theories that depict insults during early life as determinants of chronic diseases.