Postnatal Overfeeding Research Articles

Long-term impact of postnatal overfeeding on sensitivity to ischemia-reperfusion injury in vivo and on cardio-metabolism risk

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. However, these data have mainly obtained in young male mice, but less is known for older animals. Our aim was to evaluate the impact of postnatal overfeeding (PNOF) on cardiac function, on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on glucose metabolism in young (4 months), adult (6 months) and old (12 months) male mice. PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. Echocardiography and blood sugar tests have been performed at all ages. An in vivo ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h of reperfusion. All experiments have been done on 4-, 6- and 12-months aged male mice. PNOF induced an early and permanent increase in body weight in OF group, independently of mice's age (+23% at 24 days of life, +14% at 4 months, +23% at 6 and 12 months, compared to NF group). The echocardiographic measurements showed an alteration of contractile function from 6 months aged males and up to 12 months as evidenced by a decrease of the left ventricular ejection fraction (−11% for OF males from 6 to 12 months, compared to NF groups). These cardiac alterations were associated with glucose metabolism imbalance: OF males presented glucose intolerance and insulin resistance from 4 to 12 months of age. To finish, PNOF induced a significant increase of infarct size at 4 months (+37%, P < 0.01, n = 8), 6 months (+32%, P < 0.05, n = 9) and 12 months (+38%, P < 0.05, n = 9) after cardiac surgery. Nutritional programming through short-term PNOF induced an early alteration of glucose metabolism and was associated with a constant higher susceptibility to myocardial I-R injury in vivo. Moreover, PNOF mice developed altered cardiac contractility at 6 months and up to 12 months. The cellular and biochemical mechanism of these pathological modifications induced by PNOF need further exploration but could involve alterations in cardiomyocyte pathways, and/or modification of global inflammatory status.

Echocardiographic measurement of left ventricular function following myocardial infarction in adult postnatally overfed mice

Perinatal environment, such as nutritional state, is of major importance for short- and long-term cardio-metabolic status. Postnatal overfeeding (PNOF) induced in rodents by litter size reduction at birth reproduces the effects of childhood overnutrition and was shown to affect the cardiovascular function and to predispose to cardiovascular pathologies. The aim of our work was to follow the evolution of cardiac function for 60 days after in vivo myocardial infarction in control and PNOF mice. C57BL/6 male mice were raised in litter adjusted to 9 or 3 pups for control and PNOF group respectively. After weaning, mice of both groups had free access to standard diet and water. At 4 months, they were either subjected to a permanent ligation of the left anterior descending artery (LAD) to induce myocardial infarction or a sham surgery. Echocardiographic measurements were acquired at baseline and 7, 28, 45 and 60 days after surgery for cardiac function evaluation. Sixty days after surgery, the left ventricle (LV) was harvested for bio-molecular analyzes and lungs were weighed. At basal state, no difference of cardiac function was observed between the 4 groups. In both control and PNOF mice subjected to LAD ligation, the ejection fraction (EF) was significantly decreased 7 days after surgery while the systolic/diastolic LV area was significantly increased, and they both remained stable until 60 days. An increase of cardiac troponin I level and LV mass were also observed 24 h and 60 days after surgery respectively. However, no differences neither in LV contractile function nor in infarct size were noticed between control and PNOF mice. As demonstrated by the decreased LV contractility and dilation, the two groups of mice subjected to myocardial infarction developed heart failure, however, no differences between the control and PNOF groups were observed. Further experiments will be done in order to assess the cardiac expression of genes and proteins involved in heart failure, including the b-myosin heavy chain or the atrial natriuretic peptide.

Postnatal overfeeding induces higher cardiac sensitivity to in vivo ischemia-reperfusion injury at all ages in males, but only in young females

Nutritional disturbances during the postnatal period may be responsible for a predisposition in adulthood to increased cardio-metabolic risk and a greater myocardial vulnerability to ischemia. However, these data have mainly been obtained in young male mice, but less is known for females and for old animals. Evaluate the impact of postnatal overfeeding on cardiac sensitivity after in vivo ischemia reperfusion (I-R) on both sexes and in young (4 months: mths), adult (6 mths) and mature (12 mths) mice. PNOF was induced by reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) litters were composed of 9 pups/mother and overfed group litters (OF) of 3 pups/mother. The in vivo ischemia was induced by a 45 min ligation of the left anterior interventricular artery, followed by 24 hours of reperfusion, in hearts from 4-, 6- and 12-months aged male and female mice. The area at risk (AAR) was determined by Evans blue coloration and the infarct size by TTC staining. PNOF induced an early and permanent increase in body weight in OF group, for males (4 mths: +13%; 6 mths: +23%; 12 mths: +23%) and female mice (4 mths: +23%; 6 mths: +27%; 12 mths: +15%). A significant increase of infarct size was observed in hearts of overfed male mice aged at all ages (4 mths: +37%, 6 mths: +32% and 12 mths: +38% of AAR), but for females, infarct size was significant increased at 4 mths (+34%), but not at 6 and 12 mths. However, in all female groups (NF and OF) we observed a higher post-surgical mortality and a greater data variability as compared to males. Nutritional programming through short-term PNOF induced a higher susceptibility to myocardial I-R injury in vivo at all ages in male mice, but only in young females. The mechanism of this sexual dimorphism in our model is not well understood, but could involve distinct levels of cardioprotective pathways expression, related to hormonal status.

Curcumin alleviates hepatic steatosis by improving mitochondrial function in postnatal overfed rats and fatty L02 cells through the SIRT3 pathway.

Postnatal overfeeding could increase the risk of non-alcoholic fatty liver disease (NAFLD) in adulthood. This study investigated the effects of curcumin (CUR) on hepatic steatosis in postnatal overfed rats and elucidated potential mechanisms in mitochondrial functions. Male rats were adjusted to ten (normal litter, NL) or three (small litter, SL) at postnatal day 3. After weaning, NL rats were fed with normal diet (NL) or a high-fat diet (NH) for 10 weeks. SL rats were fed with normal diet (SL), a high-fat diet (SH), a normal diet supplemented with 2% CUR (SL-CUR) or a high-fat diet supplemented with 2% CUR (SH-CUR). At week 13, compared with NL rats, SL and NH rats showed increased body weight, glucose intolerance, dyslipidemia and hepatic lipid accumulation, and these changes were more obvious in SH rats. The opposite trends were observed in SL-CUR and SH-CUR rats. Moreover, CUR could preserve mitochondrial biogenesis and antioxidant response in postnatal overfed rats, and upregulated the mRNA and protein levels of SIRT3. In vitro, L02 cells were exposed to free fatty acids and/or CUR. CUR decreased the levels of cellular lipids and mitochondrial reactive oxygen species, and increased the mitochondrial DNA copy number and superoxide dismutase activity in fatty L02 cells. However, these effects were blocked after SIRT3 silencing. It was concluded that postnatal overfeeding damaged mitochondrial biogenesis and antioxidant response, and increased hepatic lipids and the severity of high-fat-induced NAFLD, while CUR alleviated hepatic steatosis, at least partially, by enhancing mitochondrial function through SIRT3.

Dietary curcumin supplementation promotes browning and energy expenditure in postnatal overfed rats

BackgroundEarly postnatal overfeeding could result in metabolic imprinting that decreases energy expenditure following white adipose tissue (WAT) gain throughout life. This research investigated whether curcumin (CUR) supplementation could promote WAT browning and activate thermogenesis in postnatal overfed rats.Methods and resultsThis study adjusted the size of litters to three (small litters, SL) or ten (normal litters, NL) to mimic early postnatal overfeeding or normal feeding from postnatal day 3. From postnatal week 3 (weaning period), SL rats were fed a standard diet (SL) or a diet supplemented with 1% (SL1% CUR) or 2% (SL2% CUR) CUR for ten weeks. At postnatal week 13, SL rats with 1% or 2% CUR supplementation had lower body weight and less WAT gain and had an increased lean mass ratio, and their glucose tolerance and blood lipid levels had recovered to normal when compared to SL rats that did not receive the supplement. Moreover, the increased heat generation were consistent with the expression levels of uncoupling protein 1 (UCP1) and other browning-related genes in the subcutaneous adipose tissue (SAT) of the SL2% CUR rats but not in the SL1% CUR rats. In addition, 2% CUR dietary supplementation enhanced the serum norepinephrine levels in SL rats, with upregulated mRNA levels of β3-adrenergic receptor (β3-AR) in SAT.ConclusionDietary CUR supplementation attenuates body fat gain and metabolic disorders in SL, which might be induced by promoting browning of SAT and energy expenditure. Moreover, the benefits were more obvious in SL with 2% CUR supplementation.

Lean in one way, in obesity another: effects of moderate exercise in brown adipose tissue of early overfed male Wistar rats.

Early postnatal overfeeding (PO) induces long-term overweight and reduces brown adipose tissue (BAT) thermogenesis. Exercise has been suggested as a possible intervention to increase BAT function. In this study, we investigated chronical effects of moderate-intensity exercise in BAT function in postnatal overfed male Wistar rats METHODS: Litters' delivery was on postnatal-day 0 - PN0. At PN2, litters were adjusted to nine (normal litter - NL) or three pups (small litter - SL) per dam. Animals were weaned on PN21 and in PN30 randomly divided into sedentary (NL-Sed and SL-Sed) or exercised (NL-Exe and SL-Exe), N of 14 litters per group. Exercise protocol started (PN30) with an effort test; training sessions were performed three times weekly at 60% of the VO2max achieved in effort test, until PN80. On PN81, a temperature transponder was implanted beneath the interscapular BAT, whose temperature was assessed in periods of lights-on and -off from PN87 to PN90. Sympathetic nerve activation of BAT was registered at PN90. Animals were euthanized at PN91 and tissues collected RESULTS: PO impaired BAT thermogenesis in lights-on (pPO < 0.0001) and -off (pPO < 0.01). Exercise increased BAT temperature in lights-on (pExe < 0.0001). In NL-Exe, increased BAT activity was associated with higher sympathetic activity (pExe < 0.05), β3-AR (pExe < 0.001), and UCP1 (pExe < 0.001) content. In SL-Exe, increasing BAT thermogenesis is driven by a combination of tissue morphology remodeling (pExe < 0.0001) with greater effect in increasing UCP1 (pExe < 0.001) and increased β3-AR (pExe < 0.001) content. Moderate exercise chronically increased BAT thermogenesis in both, NL and SL groups. In NL-Exe by increasing Sympathetic activity, and in SL-Exe by a combination of increased β3-AR and UCP1 content with morphologic remodeling of BAT. Chronically increasing BAT thermogenesis in obese subjects may lead to higher overall energy expenditure, favoring the reduction of obesity and related comorbidities.

ω3PUFAs improve hepatic steatosis in postnatal overfed rats and HepG2 cells by inhibiting acetyl-CoA carboxylase.

Postnatal overfeeding can lead to persistent increases in hepatic lipid synthesis and the risk of nonalcoholic fatty liver disease (NAFLD) in adulthood. The ω3 polyunsaturated fatty acids (ω3PUFAs) exhibit beneficial effects on NAFLD. Here, we employed a rat model and an in vitro HepG2 cell model to investigate whether fish oil (FO) affects hepatic lipid synthesis due to postnatal overfeeding. Male Sprague‐Dawley were divided into litter sizes of three (small litters, SLs) or 10 (normal litters, NLs) on postnatal day 3 and were fed standard chow or FO diet beginning on postnatal week 3 to generate NL, SL, NL‐FO, and SL‐FO groups. The results indicated that the FO diet reduced the postnatal overfeeding‐induced body weight gain and NAFLD characteristics (such as serum and liver triglyceride (TG) and hepatic steatosis). In addition, FO restored the expression of hepatic lipid metabolism‐related genes (including SCD1, FASN, CPT1, LPL, ACC, and SREBP‐1c) in SL‐FO rats. Specifically, the activity and expression pattern of ACC were consistent with SREBP‐1c. Furthermore, HepG2 cells were treated with oleic acid (OA), followed by eicosapentenoic acid (EPA), with or without SREBP‐1c siRNA. The cellular lipid droplets, TG content, and the expression of ACC (by 75%) and SREBP‐1c (by 45%) were increased by OA stimulation (p < .05), which was inhibited by EPA treatment. However, the effect of EPA treatment was abolished when SREBP‐1c was silenced. In conclusion, ω3PUFAs‐rich diet may be an effective way to reverse the developmental programming of hepatic lipid synthesis, at least partially, by inhibiting ACC through modulating SREBP‐1c.

Early postnatal overnutrition impairs VO2max gains with moderate exercise and increase post-exercise muscle damage in adult male rats.

Exercise counteracts obesity effects, but information on how early-life obesity may affect long-term adaptation to exercise is lacking. This study investigates the impact of early-life postnatal overfeeding (PO) on animals' adaptation to exercise. Only male Wistar rats were used. On postnatal day (PN) 30, rats from control (NL-9 pups) or PO (SL-3 pups) litters were separated into four groups: NL-sedentary (NL-Se), NL-exercised (NL-Ex), SL-sedentary (SL-Se), and SL-exercised (SL-Ex). Exercised groups performed moderate-intensity exercise, running on a treadmill, from PN30 to PN90. Further experiments were carried out between PN90 and PN92. PO promoted obesity in SL versus NL rats (P < 0.05). Exercise reduced body weight (P < 0.001), body fat (P < 0.01), and improved glucose homeostasis in SL-Ex versus SL-Se. SL-Ex presented lower VO2max (P < 0.01) and higher post-exercise LDH (P < 0.05) compared to NL-Ex rats. Although moderate exercise counteracted obesity in SL rats, early-life overnutrition restricts fitness gains in adulthood, indicating that early obesity may impair animals' adaptation to exercise.

Evaluation of left ventricular function following myocardial infarction in adult postnatally overfed mice

Perinatal environment, such as nutritional state, is of major importance for short- and long-term cardio-metabolic status. Postnatal overfeeding (PNOF) induced in rodents by litter size reduction at birth reproduces the effects of childhood overnutrition and was shown to affect the cardiovascular function and to predispose to cardiovascular pathologies. The aim of our work was to follow the evolution of cardiac function for 28 days after in vivo myocardial infarction in control or PNOF mice. C57BL/6 male mice were raised in litter adjusted to 9 or 3 pups for control and PNOF group respectively. After weaning, mice of both groups had free access to standard diet and water. At 4 months, they were subjected to permanent ligation of the left anterior descending artery (LAD) to induce myocardial infarction or to sham surgery. Echocardiographic measurements were acquired at baseline and 1, 7, 15 and 28 days after surgery for cardiac function evaluation. Twenty-eight days after surgery, the left ventricle (LV) and lungs were weighed and infarct size was assessed. At basal state, no difference of cardiac function was observed between the 4 groups. In both control and PNOF mice subjected to LAD ligation, the fractional area change (FAC) was significantly decreased 24 h after surgery and the systolic/diastolic LV area was significantly increased 7 d after surgery, and both remained stable until 28 d. However, no differences neither in LV contractile function nor in infarct size were noticed between control and PNOF mice, except for an increased LV mass in PNOF mice. While all groups of mice subjected to myocardial infarction developed heart failure, as demonstrated by decreased LV contractility and dilation, there were no differences between control and PNOF groups. Further measures will be done in order to assess circulating biomarkers as cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and growth differentiation factor-15 (GDF-15).

Postnatal overfeeding induces a higher cardiac sensitivity to in vivo ischemia-reperfusion injury at all ages in male mice, but only in young females

Nutritional disturbances during the postnatal period may be responsible for a predisposition in adulthood to increased cardio-metabolic risk and a greater myocardial vulnerability to ischemia. However, these data have mainly been obtained in young male mice, but less is known for females and for older animals. Evaluate the impact of postnatal overfeeding on: – cardiac sensitivity after in vivo ischemia-reperfusion (I-R) on both sexes; – in young (4 months), adult (6 months) and mature (12 months) mice. PNOF was induced by reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) litters were composed of 9 pups/mother and overfed group litters (OF) of 3 pups/mother. The in vivo ischemia was induced by a 45 min ligation of the left anterior interventricular artery, followed by 24 hours of reperfusion, in hearts from 4-, 6- and 12-months aged male and female mice. The area at risk (AAR) was determined by Evans blue coloration and the infarct size by TTC staining. PNOF induced an early and permanent increase in body weight in OF group, for males (4 months: +13%; 6 months: +23%; 12 months: +23%) and female mice (4 months: +23%; 6 months: +27%; 12 months: +15%). A significant increase of infarct size was observed in hearts of overfed male mice aged at all ages (4 months: +37%, 6 months: +32% and 12 months: +38% of AAR), but for females, infarct size was significant increased at 4 months (+34%), but not at 6 and 12 months. However, in all female groups (NF and OF) we observed a higher post-surgical mortality and a greater data variability as compared to males. Nutritional programming through short-term PNOF induced a higher susceptibility to myocardial I-R injury in vivo at all ages in male mice, but only in young females. The mechanism of this sexual dimorphism in our model is not well understood, but could involve distinct levels of cardioprotective pathways expression, related to hormonal status.

Effects of moderate intensity endurance training and high-intensity interval training on the reproductive parameters of wistar rats overfed in infancy.

Studies indicate that rapid weight gain at critical development stages, such as the lactation period, is associated with the development of obesity, cardiovascular diseases, and diabetes in the long term. In addition to metabolic changes during adulthood, overweight/obesity may influence reproductive function. Human and animal studies suggest that lifestyle changes through exercise and/or controlled diet result in improved semen quality in obese individuals. However, the relationship between exercise volume/intensity and reproductive capacity effects remains inconclusive. The present study aimed to evaluate the effects of moderate intensity endurance training and high-intensity interval training (HIIT) on the reproductive parameters of lactating overfed male Wistar rats. Postnatal overfeeding was induced by applying the litter size reduction method. Forty males Wistar rats were used, divided into four groups: one with control litters (CLs) (10 animals/litter-sedentary) and three with small litters (SLs) (4 animals/litter), divided into sedentary, moderate endurance training, and HIIT. Morphologic, metabolic, and reproductive variables were analyzed. SL sedentary group showed increased body weight, adiposity, and decreased relative weight of the seminal vesicle, prostate, and epididymis as well as changes in the insulin tolerance and oral glucose tolerance tests glycemic tests compared to CL sedentary group. Endurance and HIIT protocols were efficient in improving the glycemic metabolism, central fat accumulation of trained groups and did not affect reproductive parameters. Endurance and HIIT protocols proved to be effective in reversing these metabolic changes without impairing the evaluated reproductive parameters.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Interplay between gonadal hormones and postnatal overfeeding in defining sex-dependent differences in gut microbiota architecture

Aging is associated with a decline in sex hormones, variable between sexes, that has an impact on many different body systems and might contribute to age-related disease progression. We aimed to characterize the sex differences in gut microbiota, and to explore the impact of depletion of gonadal hormones, alone or combined with postnatal overfeeding, in rats. Many of the differences in the gut microbiota between sexes persisted after gonadectomy, but removal of gonadal hormones shaped several gut microbiota features towards a more deleterious profile, the effect being greater in females than in males, mainly when animals were concurrently overfed. Moreover, we identified several intestinal miRNAs as potential mediators of the impact of changes in gut microbiota on host organism physiology. Our study points out that gonadal hormones contribute to defining sex-dependent differences of gut microbiota, and discloses a potential role of gonadal hormones in shaping gut microbiota, as consequence of the interaction between sex and nutrition. Our data suggest that the changes in gut microbiota, observed in conditions of sex hormone decline, as those caused by ageing in men and menopause in women, might exert different effects on the host organism, which are putatively mediated by gut microbiota-intestinal miRNA cross-talk.

Sexual dimorphism in the long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo

Nutritional disturbances during the postnatal period may be responsible for a predisposition in adulthood to increased cardio-metabolic risk and a greater myocardial vulnerability to ischemia. However, these data have mainly been obtained in male mice, but less is known for females. The aim of our study was to evaluate the impact of postnatal overfeeding on cardiac sensitivity after in vivo ischemia-reperfusion (I-R) on both sexes. PNOF was induced by reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) litters were composed of 9 pups/mother and overfed group litters (OF) of 3 pups/mother. The in vivo ischemia was induced by a 45 min ligation of the left anterior interventricular artery, followed by 24 hours of reperfusion, in hearts from 4 and 6 months aged male and female mice. The area at risk (AAR) was determined by Evans blue coloration and the infarct size by TTC staining. PNOF induced an early and permanent increase in body weight in OF group, for males (4 months: +13%; 6 months: +23%) and female mice (4 months: +23%; 6 months: +27%). A significant increase of infarct size was observed in hearts of overfed male mice aged of 4 and 6 months (respectively +37% and +32% of AAR), but it was just a trend for female mice at the same age. However, postoperative mortality was higher in both female groups (NF and OF) at 4 months (44%) and 6 months (37%) of age, as compared to males (4 months: 29%; 6 months: 18%). Nutritional programming through short-term PNOF induced a higher susceptibility to myocardial I-R injury in vivo, however with different intensities according to sex in mice. The mechanism of this different sexual dimorphism in our model is not well understood, but it could involve distinct levels of cardioprotective pathways expression.

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.

Renal Programming by Transient Postnatal Overfeeding: The Role of Senescence Pathways.

BackgroundEarly nutrition influences the risk of chronic kidney diseases (CKDs) development in adulthood. Mechanisms underlying the early programming of altered renal function remain incompletely understood. This study aims at characterizing the role of cell senescence pathways in early programming of CKD after transient postnatal overfeeding.Materials and MethodsReduced litters of 3 mice pups and standard litters of 9 mice pups were obtained to induce overfed animals during lactation and control animals, respectively. Animals were sacrificed at 24 days (weaning) or at 7 months of life (adulthood). Body weight, blood pressure, kidney weight, and glomerular count were assessed in both groups. Senescence pathways were investigated using β-Galactosidase staining and Western blotting of P16, P21, P53, P-Rb/Rb, and Sirtuin 1 (Sirt1) proteins.ResultsEarly overfed animals had a higher body weight, a higher blood pressure at adulthood, and a higher glomerular number endowment compared to the control group. A higher β-Galactosidase activity, a significant increase in P53 protein expression (p = 0.0045) and a significant decrease in P-Rb/Rb ratio (p = 0.02), were observed at weaning in animals who underwent early postnatal overfeeding. Protein expression of Sirt1, a protective factor against accelerated stress-induced senescence, was significantly decreased (p = 0.03) at weaning in early overfed animals.ConclusionEarly postnatal overfeeding by litter size reduction is associated with increased expression of factors involved in cellular senescence pathways, and decreased expression of Sirt 1 in the mouse kidney at weaning. These alterations may contribute to CKD programming after early postnatal overfeeding.

Postnatal overfeeding induces hepatic microRNA-221 expression and impairs the PI3K/AKT pathway in adult male rats.

Increasing evidence suggests that postnatal overfeeding induces childhood obesity, which is strongly associated with metabolic syndrome. Insulin resistance is a risk factor for metabolic syndrome. MicroRNA-221 (miR-221) is involved in the development of obesity and has been reported to negatively regulate insulin sensitivity. However, the underlying mechanism remains unclear. Rats raised in small litters (SLs, three pups/dam, n = 10) and normal litters (NLs, 10 pups/dam, n = 10) were used to model early postnatal overfeeding and act as controls, respectively. miR-221 and proteins related to the phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT) pathway were assessed in the liver. Early postnatal overfeeding significantly increased body weight, visceral fat index, blood glucose, serum triglycerides, and the homeostasis model assessment of insulin resistance at 9 weeks. Real-time polymerase chain reaction (PCR) and western blot analysis revealed that postnatal overfeeding induced insulin receptor and insulin receptor substrate 2 expression, but decreased PI3K and AKT phosphorylation in the liver. Quantitative real-time PCR showed that hepatic miR-221 was significantly overexpressed in the SL group. These results indicate that postnatal overfeeding induces hepatic miR-221 overexpression and impairs the PI3K/AKT signal pathway, which may cause insulin resistance. We first report postnatal overfeeding induces hepatic miR-221 expression. Postnatal overfeeding impairs PI3K/AKT pathway in the liver of adult rats. Postnatal overfeeding induces obesity and high blood glucose. Avoidance of overfeeding during early postnatal life may prevent obesity and T2DM.

Renal programming by transient postnatal overfeeding: the role of senescence pathways

Renal programming by transient postnatal overfeeding: the role of senescence pathways

Omega3-polyunsaturated fatty acid ameliorates metabolic disorders in adulthood rats caused by postnatal early overfeeding

Objective To explore the effect and mechanism of omega 3-polyunsaturated fatty acid(ω3-PUFA) dietary intervention on mitochondrial function of white adipose tissue in adult rats with postnatal early overfeeding. Methods An overfed animal model by adjusting litter size was developed for the study of neonatal overfeeding. The litter size was adjusted to 3 male rats per litter(small litter, SL group) and 10 pups per litter(normal litter, NL group). After weaning(week 3), the pups were fed standard chow or ω3-PUFA diet(SL-FO) until postnatal weeks 13. Food intake, body weight, and rectal temperature of rats were measured regularly, and energy metabolism of animals was monitored in week 13. During week 3 and 13, subcutaneous adipose tissue was collected. Inguinal preadipocytes of mice were isolated and induced to differentiate, and 50 μmol/L eicosapentaenoicacid(EPA) was administered for 48 h at the late stage of differentiation. The mRNA and protein expression levels of mitochondrial related genes, mitochondrial copy number, and oxygen consumption rate of adipocytes were detected in adipose tissue and adipocytes. Results By the 3rd week, the body weight, food intake, and fat cell area in SL group were higher than those in NL group while the body temperature was lower until to 13 weeks. By the 13th week, the O2 consumption, CO2 output, and heat production of rats in SL group were lower than those in NL group. Meanwhile, the expressions of mitochondrial function related genes such as uncoupling protein 1(UCP1), carnitine palmitoyltransferase 1(CPT1), SIRT1, and mitochondrial biosynthesis regulatory gene peroxisome proliferator-activated receptor coativator-1 (PGC1α) in adipose tissue by the 3rd and 13th week were significantly reduced(P<0.05). After weaning, ω3-PUFA diet significantly reduced weight gain in SL rats, increased UCP1 protein expression, restored energy metabolism level and mitochondrial function related gene expression. In vitro intervention of EPA increased the mitochondrial copy number, the mRNA and protein expression levels of mitochondrial biosynthesis and functional genes, as well as the mitochondrial basic oxygen consumption rate(P<0.05). Conclusion ω3-PUFA improves postnatal overfeeding-induced impairment of the mitochondrial function and biosynthesis of subcutaneous white adipose tissue in rats, which may be an important mechanism for fish oil diet to inhibit the early over-nutrition program and restore the thermogenic metabolism. Key words: Omega 3-PUFA; Postnatal overfeeding; White fat; Mitochondria

Calorie Restriction in Adulthood Reduces Hepatic Disorders Induced by Transient Postnatal Overfeeding in Mice

Impaired early nutrition influences the risk of developing metabolic disorders in later life. We observed that transient postnatal overfeeding (OF) in mice induces long-term hepatic alterations, characterized by microsteatosis, fibrosis associated with oxidative stress (OS), and stress-induced premature senescence (SIPS). In this study, we investigated whether such changes can be reversed by moderate calorie restriction (CR). C57BL/6 male mice pups were maintained during lactation in litters adjusted to nine pups in the normal feeding (NF) group and three pups in the transient postnatal OF group. At six months of age, adult mice from the NF and OF groups were randomly assigned to an ad libitum diet or CR (daily energy supply reduced by 20%) for one month. In each group, at the age of seven months, analysis of liver structure, liver markers of OS (superoxide anion, antioxidant defenses), and SIPS (lipofuscin, p53, p21, p16, pRb/Rb, Acp53, sirtuin-1) were performed. CR in the OF group reduced microsteatosis, decreased levels of superoxide anion, and increased protein expression of catalase and superoxide dismutase. Moreover, CR decreased lipofuscin staining, p21, p53, Acp53, and p16 but increased pRb/Rb and sirtuin-1 protein expression. CR did not affect the NF group. These results suggest that CR reduces hepatic disorders induced by OF.