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Maternal high-fat diet regulates glucose metabolism and pancreatic ? cell phenotype in mouse offspring at weaning.

ABSTRACT: Background:Maternal malnutrition is a critical factor in determining the risk of obesity and glucose intolerance in offspring. However, little is known about the effects of a maternal high-fat diet (HFD) on the ? cell phenotype in offspring, which is a major factor in glucose homeostasis, especially during the early life of offspring. Methods:Dams were randomly fed a HFD (60% kcal from fat) or a chow diet before pregnancy and during gestation and lactation. Glucose metabolism and the ? cell phenotype were assessed in male offspring at weaning. Results:Dams fed a HFD showed impaired glucose tolerance. A HFD predisposed the offspring to increased impairment of metabolic health, including obesity, glucose intolerance and insulin resistance, compared with offspring from chow diet-fed dams. Furthermore, increased islet sizes and islet densities were observed in male offspring from HFD-fed dams at weaning. There were increases in the insulin-positive area, ? cell mass and ? cell proliferation in male offspring from HFD-fed dams at weaning age. Next, we further determined whether a maternal HFD could affect ? cell apoptosis in mouse offspring and found that there was no significant change in ? cell apoptosis between the HFD and control groups. Conclusion:Our study is novel in showing that a maternal HFD predisposes offspring to impaired glucose metabolism and has a profound effect on ? cell mass and proliferation in offspring mice, which is observed in mice as early as at weaning age. However, further study to clarify the underlying mechanisms is warranted.

SUBMITTER: Zheng J

PROVIDER: S-EPMC7316079 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Maternal high-fat diet regulates glucose metabolism and pancreatic β cell phenotype in mouse offspring at weaning.

Zheng Jia J Zhang Ling L Wang Ziwei Z Zhang Junqing J

PeerJ 20200622

<h4>Background</h4>Maternal malnutrition is a critical factor in determining the risk of obesity and glucose intolerance in offspring. However, little is known about the effects of a maternal high-fat diet (HFD) on the β cell phenotype in offspring, which is a major factor in glucose homeostasis, especially during the early life of offspring.<h4>Methods</h4>Dams were randomly fed a HFD (60% kcal from fat) or a chow diet before pregnancy and during gestation and lactation. Glucose metabolism and ...[more]

PMID: 32607287

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Project description:Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = -0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.

Project description:BackgroundCombined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated.MethodsFemale mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring.ResultsHFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho β, and its downstream targets, proliferator-activated receptor-γ co-activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring.ConclusionsLeucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.

Project description:Maternal diabetes-induced fetal programming predisposes offspring to type 2 diabetes, cardiovascular disease, and obesity in adulthood. However, lifelong health and disease trajectories depend on several factors and nutrition is one of the main ones. We intend to understand the role of maternal diabetes-induced fetal programming and its association with a high-fat diet during lifelong in the female F1 generation focusing on reproductive outcomes and the possible changes in physiological systems during pregnancy as well as the repercussions on the F2 generation at birth. For this, we composed four groups: F1 female pups from control (OC) or from diabetic dams (OD) and fed with standard (SD) or high-fat diet from weaning to full-term pregnancy. During pregnancy, glucose intolerance and insulin sensitivity were evaluated. In a full-term pregnancy, the maternal blood and liver were collected to evaluate redox status markers. The maternal blood, placental tissue, and fetal blood (pool) were collected to evaluate adiponectin and leptin levels. Maternal reproductive parameters were evaluated as well. Maternal diabetes and high-fat diet consumption, in isolation, were both responsible for increased infertility rates and fasting glucose levels in the F1 generation and fetal growth restriction in the F2 generation. The association of both conditions showed, in addition to those, increased lipoperoxidation in maternal erythrocytes, regardless of the increased endogenous antioxidant enzyme activities, glucose intolerance, decreased number of implantation sites and live fetuses, decreased litter, fetal and placental weight, increased preimplantation losses, and increased fetal leptin serum levels. Thus, our findings show that fetal programming caused by maternal diabetes or lifelong high-fat diet consumption leads to similar repercussions in pregnant rats. In addition, the association of both conditions was responsible for glucose intolerance and oxidative stress in the first generation and increased fetal leptin levels in the second generation. Thus, our findings show both the F1 and F2 generations harmed health after maternal hyperglycemic intrauterine environment and exposure to a high-fat diet from weaning until the end of pregnancy.

Project description:Dysbiosis of gut microbiota can contribute to the progression of diabetes and obesity. Previous studies have shown that maternal high-fat (HF) diet during the perinatal period can alter the microbiota and induce metabolic disorders at weaning. However, whether dysbiosis of gut microbiota and metabolism could be recovered by a normal diet after weaning and the dynamic changes of gut microbiota have not been fully studied. In this study, C57BL/6J female mice were fed with a normal chow (NC) or HF diet for 4 weeks preconception, during gestation, and until pup weaning. After weaning, male offspring were fed with an NC diet until 9 weeks of age. The microbiota of offspring at weaning and 9 weeks of age was collected for 16S rRNA gene amplicon sequencing. We found that dams fed with an HF diet showed glucose intolerance after lactation. Compared with the offspring from NC dams, the offspring from HF dams exhibited a higher body weight, hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia, and leptin resistance and lower adiponectin at weaning. Fecal analysis indicated altered microbiota composition between the offspring of the two groups. The decrease in favorable bacteria (such as norank f Bacteroidales S24-7 group) and increase in unfavorable bacteria (such as Lachnoclostridium and Desulfovibrio) were strongly associated with a disturbance of glucose and lipid metabolism. After 6 weeks of normal diet, no difference in body weight, glucose, and lipid profiles was observed between the offspring of the two groups. However, the microbiota composition of offspring in the HF group was still different from that in the NC group, and microbiota diversity was lower in offspring of the HF group. The abundance of Lactobacillus was lower in the offspring of the HF group. In conclusion, a maternal HF diet can induce metabolic homeostasis and gut microbiota disturbance in offspring at weaning. Gut microbiota dysbiosis can persist into adulthood in the offspring, which might have a role in the promotion of susceptibility to obesity and diabetes in the later life of the offspring.

Dataset Information

Maternal high-fat diet regulates glucose metabolism and pancreatic ? cell phenotype in mouse offspring at weaning.

Publications

Maternal high-fat diet regulates glucose metabolism and pancreatic β cell phenotype in mouse offspring at weaning.

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