Combined maternal and postnatal high-fat diet leads to metabolic syndrome and is effectively reversed by resveratrol: a multiple-organ study.
ABSTRACT: This study aimed to study the impact of a combination of maternal and post-weaning high-fat diets and whether resveratrol was beneficial. Sprague-Dawley dams were fed either chow or a high-fat diet, before mating, during pregnancy, and into lactation. At weaning, their offspring were randomly fed chow or a high-fat diet. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal high-fat/postnatal chow diet), CH (maternal chow/postnatal high-fat diet), and HH (maternal/postnatal high-fat diet). A fifth group consisted of HH plus resveratrol. The 4 month-old offspring of HH group had higher body weight, higher levels of plasma triglycerides, leptin, angiotensin I and angiotensin II and abnormal intraperitoneal glucose tolerance test results, which fulfilled the features of metabolic syndrome. The dysregulation of the renin-angiotensin system was seen in multiple organs. Sirtuin 1 expression/abundance was reduced by a maternal/postnatal high-fat diet, in all the organs examined. Resveratrol ameliorated most of the features of metabolic syndrome and molecular alterations. The administration of a high-fat diet in both periods showed interactive metabolic effects in the plasma and many organs. Our results suggest that a maternal high-fat diet sensitizes offspring to the adverse effects of subsequent high-fat intake on multiple organs.
Project description:Obesity during pregnancy increases the risk of cardiovascular problems, diabetes, asthma, and cognitive impairments, affecting the offspring. It is important to reduce the negative effects of obesity and high-fat (HF) diet during pregnancy. We employed a rat model of maternal HF diet to evaluate the possible de-programming effects of resveratrol in rodent male offspring with maternal HF diet/obesity. Male rat offspring were randomized into four groups: maternal control diet/postnatal control diet, maternal HF diet/postnatal control diet, maternal control diet plus maternal resveratrol treatment/postnatal control diet, and maternal HF diet plus maternal resveratrol treatment/postnatal control diet. Maternal HF diet during pregnancy plus lactation resulted in retroperitoneal adiposity in the male offspring. Maternal resveratrol treatment re-programmed maternal HF exposure-induced visceral adiposity. Offspring that received prenatal HF diet showed higher leptin/soluble leptin receptor (sOB-R) ratio than offspring that received prenatal control diet. Maternal resveratrol treatment ameliorated maternal HF exposure-induced increase in leptin/sOB-R ratio and altered the expression of genes for crucial fatty acid synthesis enzymes in the offspring. Thus, maternal resveratrol administration reduces retroperitoneal adiposity in rat offspring exposed to prenatal HF diet/obesity and could be used to ameliorate negative effects of maternal HF diet in the offspring.
Project description:Maternal diet and gestational hyperglycaemia have implications for offspring health. Leptin (LEP) and fat mass and obesity-associated (FTO) alleles are known to influence body fat mass in humans, potentially via effects on appetite. We hypothesized that expression of Fto, Lep, and other appetite-related genes (Argp, Npy, Pomc, Cart, Lepr) in the offspring of female mice are influenced by the glycaemic index (GI) of carbohydrates in the maternal diet. C57BL/6 mice were randomly assigned to low or high GI diets and mated with chow-fed males at eight weeks of age. Male pups were weaned at four weeks and randomly divided into two groups, one group following their mother's diet (LL and HH), and one following the standard chow diet (LC and HC) to 20 weeks. Fto expression was 3.8-fold higher in the placenta of mothers fed the high GI diet (p = 0.0001) and 2.5-fold higher in the hypothalamus of 20-week old offspring fed the high GI (HH vs. LL, p < 0.0001). By contrast, leptin gene (Lep) expression in visceral adipose tissue was 4.4-fold higher in four-week old offspring of low GI mothers (LC vs. HC, p < 0.0001) and 3.3-fold higher in visceral adipose tissue of 20-week old animals (LL vs. HH, p < 0.0001). Plasma ghrelin and leptin levels, and hypothalamic appetite genes were also differentially regulated by maternal and offspring diet. These findings provide the first evidence in an animal model that maternal high GI dietary carbohydrates that are digested and absorbed faster may contribute to programming of appetite in offspring.
Project description:Maternal high-fat or high-salt diets can independently program adverse cardiometabolic outcomes in offspring. However, there is a paucity of evidence examining their effects in combination on metabolic function in adult offspring. Female Sprague Dawley rats were randomly assigned to either: control (CD; 10% kcal from fat, 1% NaCl), high-salt (SD; 10% kcal from fat, 4% NaCl), high-fat (HF; 45% kcal from fat, 1% NaCl) or high-fat and salt (HFSD; 45% kcal from fat, 4% NaCl) diets 21?days prior to mating and throughout pregnancy and lactation. Male offspring were weaned onto a standard chow diet and were culled on postnatal day 130 for plasma and tissue collection. Adipocyte histology and adipose tissue, liver, and gut gene expression were examined in adult male offspring. HF offspring had significantly greater body weight, impaired insulin sensitivity and hyperleptinemia compared to CD offspring, but these increases were blunted in HFSD offspring. HF offspring had moderate adipocyte hypertrophy and increased expression of the pre-adipocyte marker Dlk1. There was a significant effect of maternal salt with increased hepatic expression of Dgat1 and Igfb2. Gut expression of inflammatory (Il1r1, Tnf?, Il6, and Il6r) and renin-angiotensin system (Agtr1a, Agtr1b) markers was significantly reduced in HFSD offspring compared to HF offspring. Therefore, salt mitigates some adverse offspring outcomes associated with a maternal HF diet, which may be mediated by altered adipose tissue morphology and gut inflammatory and renin-angiotensin regulation.
Project description:Adequate maternal supply and placental delivery of long chain polyunsaturated fatty acids (LCPUFA) is essential for normal fetal development. In humans, maternal obesity alters placental FA uptake, though the impact of diet remains uncertain. The fatty fetal liver observed in offspring of Japanese macaques fed a high fat diet (HFD) was prevented with resveratrol supplementation during pregnancy. We sought to determine the effect of HFD and resveratrol, a supplement with insulin-sensitizing properties, on placental LCPUFA uptake in this model.J. macaques were fed control chow (15% fat, n = 5), HFD (35% fat, n = 10) or HFD containing 0.37% resveratrol (n = 5) prior to- and throughout pregnancy. At ? 130 d gestation (term = 173 d), placentas were collected by caesarean section. Fatty acid uptake studies using (14)C-labeled oleic acid, arachidonic acid (AA) and docosahexanoic acid (DHA) were performed in placental explants.Resveratrol supplementation increased placental uptake of DHA (P < 0.05), while HFD alone had no measurable effect. Resveratrol increased AMP-activated protein kinase activity and mRNA expression of the fatty acid transporters FATP-4, CD36 and FABPpm (P < 0.05). Placental DHA content was decreased in HFD dams; resveratrol had no effect on tissue fatty acid profiles.Maternal HFD did not significantly affect placental LCPUFA uptake. Furthermore, resveratrol stimulated placental DHA uptake capacity, AMPK activation and transporter expression. Placental handling of DHA is particularly sensitive to the dramatic alterations in the maternal metabolic phenotype and placental AMPK activity associated with resveratrol supplementation.
Project description:Resveratrol has been proposed as a potential therapeutic to improve metabolic health during pregnancy, yet little is known about the fetal effects of this maternal dietary supplement. We hypothesized that when administered to pregnant nonhuman primates (NHPs), resveratrol would increase uterine blood flow and mitigate the harmful consequences of maternal Western-style diet (WSD) consumption. NHPs were fed a WSD (36% fat) supplemented with 0.37% resveratrol throughout pregnancy. Outcomes were compared with cohorts fed WSD alone and control chow (14% fat) to distinguish between WSD and resveratrol-specific effects in these animals. In the early third trimester, uterine blood flow was measured by Doppler ultrasound before fetal delivery and tissue collection. Resveratrol resulted in 30% maternal weight loss and improved glucose tolerance, increased uterine artery volume blood flow, and decreased placental inflammation and liver triglyceride deposition. In addition, fetal pancreatic mass was enlarged by 42%, with a 12-fold increase in proliferation by Ki67 immunohistochemistry. These results demonstrate that resveratrol use during pregnancy yields improvements in maternal and placental phenotype with beneficial effects in the fetal liver but an unexplained and concerning alteration in fetal pancreatic development, which strongly cautions against the use of resveratrol by pregnant women.
Project description:Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.
Project description:Promoting the browning of white fat may be a potential means of combating obesity. Therefore, in this study, we investigated the effect of resveratrol (RES) on the body weight and browning of white fat in high-fat diet (HFD)-induced obese mice and the potential associated mechanism in vivo. Eight-week-old male mice were randomized to receive different treatments: (1), chow without any additional treatment (chow); (2), chow plus 0.4% resveratrol (chow-RES); (3), HFD without any additional treatment (HFD); and (4), HFD plus 0.4% resveratrol (HFD-RES). After 4 weeks of feeding, additional 8-week-old male recipient mice were randomly allocated to the following 4 treatments: (5), HFD and received feces from chow-fed mice; (6), HFD and received feces from chow-RES-fed mice; (7), HFD and received feces from HFD-fed mice; and (8), HFD and received feces from HFD-RES-fed mice. RES treatment significantly inhibited increases in fat accumulation, promoted the browning of white adipose tissue (WAT) and alleviated gut microbiota dysbiosis in HFD-fed mice. Subsequent analyses showed that the gut microbiota remodeling induced by resveratrol had a positive role in WAT browning, and sirtuin-1 (Sirt1) signaling appears to be a key component of this process. Overall, the results show that RES may serve as a potential intervention to reduce obesity by alleviating dysbiosis of the gut microbiota.
Project description:OBJECTIVE:Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY) and suppressor proopiomelanocortin (POMC) in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD) consumption are unclear. RESEARCH DESIGN AND METHODS:Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control). At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid) metabolic markers were measured. RESULTS:Offspring from obese dams gained more weight than those from lean dams independent of post-weaning diet. Maternal obesity interacted with post-weaning HFD consumption to cause greater levels of hyperphagia, adiposity, hyperlipidemia, and glucose intolerance in offspring. This was linked to increased hypothalamic NPY signaling and leptin resistance in adult offspring. Litter size reduction had a detrimental impact on insulin and adiponectin, while hypothalamic NPY and POMC mRNA expression were suppressed in the face of normal energy intake and weight gain. CONCLUSIONS:Maternal obesity, postnatal litter size reduction and post-weaning HFD consumption caused obesity via different neuroendocrine mechanism. There were strong additive effects of maternal obesity and post-weaning HFD consumption to increase the metabolic disorders in offspring.
Project description:Poor maternal diet can lead to metabolic disease in offspring, whereas maternal exercise may have beneficial effects on offspring health. In this study, we determined ifmaternal exercise could reverse the detrimental effects of maternal high-fat feeding on offspring metabolism of female mice. C57BL/6 female mice were fed a chow (21%) or high-fat (60%) diet and further divided by housing in static cages or cages with running wheels for 2 weeks prior to breeding and throughout gestation. Females were bred with chow-fed sedentary C57BL/6 males. High fat-fed sedentary dams produced female offspring with impaired glucose tolerance compared with offspring of chow-fed dams throughout their first year of life, an effect not present in the offspring from high fat-fed dams that had trained. Offspring from high fat-fed trained dams had normalized glucose tolerance, decreased fasting insulin, and decreased adiposity. Liver metabolic function, measured by hepatic glucose production in isolated hepatocytes, hyperinsulinemic-euglycemic clamps, liver triglyceride content, and liver enzyme expression, was enhanced in offspring from trained dams. In conclusion, maternal exercise negates the detrimental effects of a maternal high-fat diet on glucose tolerance and hepatocyte glucose metabolism in female offspring. The ability of maternal exercise to improve the metabolic health of female offspring is important, as this intervention could combat the transmission of obesity and diabetes to subsequent generations.
Project description:Obesity poses a significant risk of developing type II diabetes and other diseases. Hedgehog (Hh) signaling has been shown to inhibit adipose tissue development, but its effect on diet-induced obesity during postnatal life is not known. Here by inducing expression of constitutively active Smoothened (SmoM2) or Gli2 (?NGli2) in the adipocyte lineage of postnatal mice, we show that targeted activation of Hh signaling suppresses high-fat-diet-induced obesity and improves whole-body glucose tolerance and insulin sensitivity. Both SmoM2 and ?NGli2 induce the expression of Wnt6, a known anti-adipogenic factor, in fat depots of the mouse. Hh-Gli2 signaling inhibits not only adipocyte differentiation but also lipogenesis in adipocytes in vitro. Finally, pharmacological inhibition of Porcupine, an acyltransferase essential for Wnt secretion, alleviates both anti-adipogenic and anti-lipogenic effects of Hh in cell culture models. Overall, targeted activation of Hh signaling ameliorates diet-induced obesity and may be explored for pharmaceutical development.