Neonatal leptin treatment programmes leptin hypothalamic resistance and intermediary metabolic parameters in adult rats

We previously showed that neonatal leptin treatment programmes higher body weight and food intake in adult rats. Here we investigate whether leptin treatment during lactation affects the anorectic effect of leptin on adult rats and their hypothalamic leptin receptors (OB-Rb) and whether those changes could have consequences on intermediary metabolism. When the offspring were born, pups were divided into two groups: the Lep group, injected daily with leptin (8 microg/100 g body weight, subcutaneously) for the first 10 d of lactation, and the control group, injected daily with saline. After weaning (day 21), body weight and food intake were monitored until the rats were 150 d old. Food intake was higher in the Lep group (approximately 14 %, P<0.05) from day 133 onwards, and body weight was higher (approximately 10 %, P<0.05) from day 69 onwards, compared with the control group. At 150 d of age, the rats were tested for food intake in response to either leptin (0.5 mg/kg body weight intraperitoneally; groups CL and LepL) or saline (groups CSal and LepSal). The CL group showed a decrease in food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group demonstrated a decrease in OB-Rb expression (-40 %, P<0.05), hyperleptinaemia (+78 %, P<0.05), hyperinsulinaemia (+100 %, P<0.02), hypertriacylglycerolaemia (+17 %, P<0.05) and a higher protein content in the body (+16 %, P<0.05) without changes in fat mass and glycaemia. We conclude that neonatal leptin treatment programmes both hyperleptinaemia and hyperinsulinaemia in adulthood, which leads to leptin resistance by reducing the expression of the hypothalamic leptin receptor.     

Effect of maternal protein restriction during pregnancy and postweaning high-fat feeding on diet-induced thermogenesis in adult mouse offspring

Purpose

Prenatal undernutrition followed by postweaning feeding of a high-fat diet results in obesity in the adult offspring. In this study, we investigated whether diet-induced thermogenesis is altered as a result of such nutritional mismatch.

Methods

Female MF-1 mice were fed a normal protein (NP, 18 % casein) or a protein-restricted (PR, 9 % casein) diet throughout pregnancy and lactation. After weaning, male offspring of both groups were fed either a high-fat diet (HF; 45 % kcal fat) or standard chow (C, 7 % kcal fat) to generate the NP/C, NP/HF, PR/C and PR/HF adult offspring groups (n = 7–11 per group).

Results

PR/C and NP/C offspring have similar body weights at 30 weeks of age. Postweaning HF feeding resulted in significantly heavier NP/HF offspring (P < 0.01), but not in PR/HF offspring, compared with their chow-fed counterparts. However, the PR/HF offspring exhibited greater adiposity (P < 0.01) v the NP/HF group. The NP/HF offspring had increased energy expenditure and increased mRNA expression of uncoupling protein-1 and β-3 adrenergic receptor in the interscapular brown adipose tissue (iBAT) compared with the NP/C mice (both at P < 0.01). No such differences in energy expenditure and iBAT gene expression were observed between the PR/HF and PR/C offspring.

Conclusions

These data suggest that a mismatch between maternal diet during pregnancy and lactation, and the postweaning diet of the offspring, can attenuate diet-induced thermogenesis in the iBAT, resulting in the development of obesity in adulthood.     

Supplementation of bitter melon to rats fed a high-fructose diet during gestation and lactation ameliorates fructose-induced dyslipidemia and hepatic oxidative stress in male offspring

This study examined the impact of maternal high-fructose intake and if metabolic control in the offspring could benefit from supplementing bioactive food components such as bitter melon (BM) to the maternal diet. In Expt. 1, virgin female rats received control (C), high-fructose (F; 60%), or BM-supplemented fructose (FBM; 1%) diet before conception until d 21 of lactation. Weaned male offspring were fed the C diet for 11 wk, forming C/C, F/C, and FBM/C groups. The F/C group had elevated serum insulin, TG, and FFA concentrations and hepatic lipid alterations compared with the C/C and FBM/C groups (P < 0.05). The 2 latter groups did not differ. Expt. 2 had similar dam treatment groups, but offspring were weaned to the C or F diet, forming C/C, C/F, F/F, and FBM/F groups, and the dietary treatment was extended to 20 wk. The hepatic levels of stearyl-CoA desaturase and microsomal TG transfer protein mRNA were lower, but that of PPARγ coactivator 1-α and fibroblast growth factor 21 mRNA and fatty acid binding protein 1 protein were higher in the FBM/F group compared with the C/F and F/F groups (P < 0.05), indicating that maternal BM supplementation may reduce lipogenesis and promote lipid oxidation in offspring. The FBM/F group had significantly higher activities of liver glutathione peroxidase, superoxide dismutase, and catalase than the F/F group. The results indicate that supplementing BM to dams could offset the adverse effects of maternal high-fructose intake on lipid metabolism and antioxidant status in adult offspring.     

Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring

Induction of an altered phenotype by prenatal under-nutrition involves changes in the epigenetic regulation of specific genes. We investigated the effect of feeding pregnant rats a protein-restricted (PR) diet with different amounts of folic acid on the methylation of individual CpG dinucleotides in the hepatic PPAR alpha promoter in juvenile offspring, and the effect of the maternal PR diet on CpG methylation in adult offspring. Pregnant rats (five per group) were fed 180 g/kg casein (control) or 90 g/kg casein with 1 mg/kg folic acid (PR), or 90 g/kg casein and 5 mg/kg folic acid (PRF). Offspring were killed on postnatal day 34 (five males and females per group) and day 80 (five males per group). Methylation of sixteen CpG dinucleotides in the PPAR alpha promoter was measured by pyrosequencing. Mean PPAR alpha promoter methylation in the PR offspring (4.5 %) was 26 % lower than controls (6.1 %) due to specific reduction at CpG dinucleotides 2 (40 %), 3 (43 %), 4 (33 %) and 16 (48 %) (P < 0.05). There was no significant difference in methylation at these CpG between control and PRF offspring. Methylation of CpG 5 and 8 was higher (47 and 63 %, respectively, P < 0.05) in the PRF offspring than control or PR offspring. The methylation pattern in day 80 PR offspring was comparable to day 34 PR offspring. These data show for the first time that prenatal nutrition induces differential changes to the methylation of individual CpG dinucleotides in juvenile rats which persist in adults.     

孕期高中链脂肪膳食对后代UCP3基因的影响

目的:探讨孕期膳食对子代肥胖和肥胖相关基因解偶联蛋白3(UCP3)表达的影响,寻找肥胖预防和治疗的靶标。方法:W istar孕鼠分别食用标准膳食和高中链脂肪膳食,所产雄性子鼠分别为对照组和高中链脂肪酸组(HMCFA),3周断乳后大鼠均食用标准膳食至成年,将对照组的大鼠随机分为两组:一组继续食用标准膳食;另一组为高脂对照组(HFCON),HFCON和HMCFA组的大鼠均高脂膳食诱导肥胖6周。分别在大鼠出生、断乳、成年、高脂诱导肥胖后各处死一批大鼠,取褐色脂肪检测UCP3 mRNA的表达。结果:与孕期标准膳食的子代相比,孕期高中链脂肪膳食可持续降低子代大鼠的体重和肥胖率(P<0.05),同时也可持续升高UCP3 mRNA的表达。结论:孕期高中链脂肪膳食可降低子代成年高脂诱导肥胖的发生;其机制为通过程序性升高子代UCP3基因的表达增加脂肪氧化和热能散失。     

Soya protein- and casein-based nutritionally complete diets fed during gestation and lactation differ in effects on characteristics of the metabolic syndrome in male offspring of Wistar rats

The AIN-93G diets based on soya protein or casein were fed to pregnant Wistar rats from day 3 of gestation and compared for their effects on characteristics of the metabolic syndrome in male offspring. Pregnant rats were randomised to either a casein (C) or soya protein (S) diet (n 12) during gestation only (Expt 1) or during gestation and lactation (Expt 2). Male offspring were weaned to either a C or S diet for 9 weeks (Expt 1) or 15 weeks (Expt 2). In Expt 1, pups born to S-fed dams had higher fasting blood glucose (BG), systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 4, higher blood glucose (BG) response to a glucose administration (P?相似文献   

Azuki bean polyphenols intake during lactation upregulate AMPK in male rat offspring exposed to fetal malnutrition

ObjectiveFetal malnutrition is an early-life inducer of dyslipidemia and glucose intolerance. The aim of this study was to examine whether maternal azuki bean (Vigna angularis) polyphenol (AP) intake during lactation affects the adenosine monophosphate–activated protein kinase (AMPK) pathway and lipid metabolism in offspring exposed to fetal malnutrition.MethodsPregnant Wistar rats were divided into three groups: a control diet offered during gestation and lactation (CC), a low-protein diet during gestation and a control diet during lactation (LPC); and a low-protein diet during gestation and a 1.0% AP-containing control diet during lactation (LPAP). Male pups were randomly selected for the study; half the pups were sacrificed at 3 wk of age and the other half were fed a standard diet and sacrificed at 23 wk. Hepatic triacylglycerol levels, phosphorylation levels of AMPK and acetyl-coenzyme A carboxylase (ACC), and mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c) were evaluated.ResultsSignificant decreases in body weights and hepatic triacylglycerol levels were found in the LPAP compared with the LPC group. Plasma adiponectin levels in the LPAP group were higher than those in the LPC group. AMPK phosphorylation was upregulated in the livers and skeletal muscles in young and adult LPAP compared with LPC rats. ACC phosphorylation was upregulated in skeletal muscles of LPAP rats. SREBP-1c mRNA expression was decreased in the livers of LPAP rats.ConclusionOur results suggest that maternal AP intake during lactation upregulates AMPK phosphorylation not only in young but also in adult offspring exposed to fetal malnutrition and may lead to decreased hepatic lipid accumulation by ACC phosphorylation and downregulation of SREBP-1c expression.     

Maternal Metformin Treatment during Gestation and Lactation Improves Skeletal Muscle Development in Offspring of Rat Dams Fed High-Fat Diet

Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring’s skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.     

A maternal high-fat diet represses the expression of antioxidant defense genes and induces the cellular senescence pathway in the liver of male offspring rats

Maternal high-fat (HF) diet feeding is associated with increased risk of developing metabolism-related diseases in adult offspring, including chronic liver disease. The present study tested the hypothesis that maternal HF diet leads to a decreased antioxidant defense capacity and causes cellular senescence in liver of adult offspring rats, which might increase risk of developing chronic liver disease. Timed-pregnant Sprague Dawley rats were fed a HF diet (45% of energy from fat) or a control (C) diet (16% of energy from fat) during gestation and lactation. The resulting offspring were fed a C diet after weaning to generate 2 offspring groups: C diet-fed offspring of dams fed C diet (C/C) and C diet-fed offspring of dams fed a HF diet (HF/C). At 12 wk of age, male rats were killed and samples were collected for analysis. Maternal HF diet significantly increased plasma TG and hepatic TBARS concentrations and the size of hepatic lipid droplets in offspring rats. The expression of antioxidant defense genes, such as glutathione peroxidase-1, Cu/Zn superoxide dismutase (Sod1), paraoxonase enzymes (Pon1, Pon2, and Pon3), were significantly lower in the liver of HF/C pups than in C/C pups. The expression of Inhibitor of cyclin dependent Kinase 4a (p16INK4a), a marker of cellular senescence, and cyclooxygenase-2 (Cox2), a proinflammatory marker, was significantly higher in the HF/C offspring group than in the C/C offspring group. Western-blot analysis shows that cyclin D1 and phosphorylated retinoblastoma protein were significantly lower in HF/C offspring than in C/C offspring. The results provide the first evidence to our knowledge that maternal HF diet might alter antioxidant defense capacity and program the p16INK4a-dependent cellular senescence in the liver of adult offspring.     

Effect of dietary soluble fiber on neurohormonal profiles in serum and brain of rats

This study was conducted to investigate the effect of dietary soluble fiber administration and /or high fat diet on serum and brain neurohormonal profiles, adipose tissue mass and body weight gain in Sprague-Dawley rats. Four groups of rats were respectively fed 10% fat diet (C), 10% fat plus pectin diet (P), 20% fat diet (HFC) and 20% fat plus pectin diet (HFP) for 4 weeks. In HFP group, the food and energy intake, body weight gain, FER including fecal excretion were the smallest (p<0.05). Serum HDL-cholesterol, triglyceride and glucose level were also the lowest in HFP group (p<0.05). The weight of brain, epididymal fat pad and adrenal gland except liver didn''t show any significant differences among groups. Interestingly serum norepinephrine concentration of HFP group tended to be higher, but dopamine concentration tended to be lower than those of HFC group. However serum catecholamine concentration didn''t show any significant differences among all groups. Norepinephrine and epinephrine contents of right portion of midbrain of P and HFP groups were remarkably lower than those of the C group. These results suggested that soluble fiber pectin consumption might affect neurohormonal profiles in serum and brain according to dietary fat level.     

Maternal Linoleic Acid Overconsumption Alters Offspring Gut and Adipose Tissue Homeostasis in Young but Not Older Adult Rats

Maternal n-6 polyunsaturated fatty acids (PUFA) consumption during gestation and lactation can predispose offspring to the development of metabolic diseases such as obesity later in life. However, the mechanisms underlying the potential programming effect of n-6 PUFA upon offspring physiology are not yet all established. Herein, we investigated the effects of maternal and weaning linoleic acid (LA)-rich diet interactions on gut intestinal and adipose tissue physiology in young (3-month-old) and older (6-month-old) adult offspring. Pregnant rats were fed a control diet (2% LA) or an LA-rich diet (12% LA) during gestation and lactation. At weaning, offspring were either maintained on the maternal diet or fed the other diet for 3 or 6 months. At 3 months of age, the maternal LA-diet favored low-grade inflammation and greater adiposity, while at 6 months of age, offspring intestinal barrier function, adipose tissue physiology and hepatic conjugated linoleic acids were strongly influenced by the weaning diet. The maternal LA-diet impacted offspring cecal microbiota diversity and composition at 3 months of age, but had only few remnant effects upon cecal microbiota composition at 6 months of age. Our study suggests that perinatal exposure to high LA levels induces a differential metabolic response to weaning diet exposure in adult life. This programming effect of a maternal LA-diet may be related to the alteration of offspring gut microbiota.     

Differential Effects of Maternal High Fat Diet During Pregnancy and Lactation on Taste Preferences in Rats

Maternal intake of high fat diet (HFD) increases risk for obesity and metabolic disorders in offspring. Developmental programming of taste preference is a potential mechanism by which this occurs. Whether maternal HFD during pregnancy, lactation, or both, imposes greater risks for altered taste preferences in adult offspring remains a question, and in turn, was investigated in the present study. Four groups of offspring were generated based on maternal HFD access: (1) HFD during pregnancy and lactation (HFD); (2) HFD during pregnancy (HFD-pregnancy); (3) HFD during lactation (HFD-lactation); and (4) normal diet (ND) during pregnancy and lactation (ND). Adult offspring 70 days of age underwent sensory and motivational taste preference testing with various concentrations of sucrose and Intralipid solutions using brief-access automated gustometers (Davis-rigs) and 24 h two-bottle choice tests, respectively. To control for post-gestational diet effects, offspring in all experimental groups were weaned on ND, and did not differ in body weight or glucose tolerance at the time of testing. Offspring exposed to maternal HFD showed increased sensory taste responses for 0.3, 0.6, 1.2 M sucrose solutions in HFD and 0.6 M in HFD-pregnancy groups, compared to animals exposed to ND. Similar effects were noted for lower concentrations of Intralipid in HFD (0.05, 0.10%) and HFD-pregnancy (0.05, 0.10, 0.5%) groups. The HFD-lactation group showed an opposite, diminished responsiveness for sucrose at the highest concentrations (0.9, 1.2, 1.5 M), but not for Intralipid, compared to ND animals. Extended-access two-bottle tests did not reveal major difference across the groups. Our study shows that maternal HFD during pregnancy and lactation has markedly different effects on preferences for palatable sweet and fatty solutions in adult offspring and suggests that such developmental programing may primarily affect gustatory mechanisms. Future studies are warranted for determining the impact of taste changes on development of obesity and metabolic disorders in a “real” food environment with food choices available, as well as to identify specific underlying mechanisms.     

Early exposure of dams to a westernized diet has long-term consequences on food intake and physiometabolic homeostasis of the rat offspring

This study evaluated the long-term effects of a westernized diet during pregnancy and lactation. Female Wistar rats (n?=?12) were divided into two groups according to their food intake, namely, control (C) or westernized (W) diet, throughout pregnancy/lactation. On the 21st day, the male pups were weaned on a standard diet as follows: Control diet (CC) (n?=?8) and westernized diet in perinatal life followed by control diet post weaning (WC) (n?=?8). The levels of fasting (12?h) serum glucose, triglycerides (TG), and total cholesterol and fraction in the pups were determined. During weaning, the WC group showed 14% greater body weight (p?相似文献   

Dietary soya protein during pregnancy and lactation in rats with hereditary kidney disease attenuates disease progression in offspring

Dietary soya protein substitution for casein initiated at weaning slows disease progression in animal models of chronic renal disease. As there is increasing evidence that fetal programming can have a significant impact on kidney physiology and function in offspring, the objective of the current study was to determine whether exposure to soya protein in the diet earlier than weaning would have further benefits. Han:SPRD-cy (cy/+) breeder rats were fed a casein-based or soya protein-based diet 2 weeks prior to mating, throughout pregnancy and during lactation. Following this maternal period, 3-week-old pups were given either the same or the alternate diet for a 7-week weaning period. Dietary soya protein compared with casein in the maternal or weaning period both independently resulted in less renal inflammation (macrophage infiltration lower by 24% (P=0.0003) and 32% (P<0.001), respectively). When soya protein was given in both feeding periods, the effect was additive. Soya protein substitution for casein resulted in less oxidative damages as indicated by 28% lower oxidized-LDL staining (P=0.013) when present in the maternal period, or in the weaning period (by 56%, P<0.0001). Renal cell proliferation was reduced by 29-33% (P<0.05) in rats given soya protein whether the exposure was during the maternal or weaning period. Soya protein compared with casein in the maternal period also resulted in 33% (P=0.0013) less proteinuria, indicating superior renal function. Dietary soya protein during pregnancy and lactation represents a potential preventative approach in treating for those with congenital kidney diseases.     

Maternal protein restriction during pregnancy and lactation in rats imprints long-term reduction in hepatic lipid content selectively in the male offspring

Maternal protein restriction during pregnancy and lactation reduces whole body lipid stores and alters lipid homeostasis in the adult offspring. Lipid homeostasis in the body is regulated, in part, by the liver via the metabolic processes of synthesis and utilization of lipids. The present study tested the hypothesis that maternal protein restriction will imprint changes in hepatic lipid metabolism and thereby alter the hepatic lipid content of the adult offspring. Pregnant rats were fed purified diets containing 19% protein (control group) or 8% protein (low-protein group) throughout pregnancy and lactation. On day 28, pups from both groups were weaned onto regular laboratory chow. On days 65 and 150, male and female pups from each litter in both groups were killed and blood and liver collected. Maternal protein restriction was found to reduce birth weight and produce long-term reduction in the body weight of the offspring. On day 65, liver triglyceride content was decreased by 40% in the male offspring that were fed a low-protein diet. The reduction in liver triglyceride content persisted until day 150, at which time it was accompanied by decreases in hepatic cholesterol content. No such changes were observed in the female offspring. To determine if the alterations in liver lipid content resulted in compensatory changes in liver carbohydrate stores, hepatic glycogen content was measured in male offspring. Hepatic glycogen content was similar between the 2 groups on days 65 and 150. In conclusion, the present study in rats showed that maternal protein restriction during pregnancy and lactation imprints long-term changes in hepatic lipid content selectively in the male offspring.