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Maternal metabolism dysregulation during pregnancy predisposes offspring to major diseases, including hypertension, in later life, but the mechanism involved remains to be fully elucidated. A high-fat-diet (HFD) pregnant rat model was used to investigate whether excessive intrauterine lipid exposure was associated with elevated blood pressure in offspring and increased levels of leptin, an important biomarker and mediator of vascular dysfunction and hypertension. We found that gestational hyperlipidemia predisposed offspring to blood pressure elevation and sustained increases in leptin levels with no difference in body weight in the rat model. Increased leptin expression and leptin promoter hypomethylation were found in adipose tissues of HFD-exposed offspring. The treatment of mesenchymal stem cells with free fatty acids during adipogenic differentiation resulted in increased leptin expression, accompanied by leptin promoter hypomethylation. In addition, we also followed up 121 children to evaluate the association between maternal triglyceride levels and offspring blood pressure. Consistent with the animal study results, we observed elevated serum leptin levels and blood pressure in the offspring born to women with gestational hypertriglyceridemia. Our findings provide new insights that maternal hyperlipidemia is associated with elevated blood pressure in offspring and is associated with increases in leptin levels through epigenetic memory.

Background Excessive androgen exposure during pregnancy has been suggested to induce diabetic phenotypes in offspring in animal models. The aim of this study was to investigate whether pregestational maternal hyperandrogenism in human influenced the glucose metabolism in offspring via epigenetic memory from mother's oocyte to child's somatic cells. Methods Of 1782 reproductive-aged women detected pregestational serum androgen, 1406 were pregnant between 2005 and 2010. Of 1198 women who delivered, 1116 eligible mothers (147 with hyperandrogenism and 969 normal) were recruited. 1216 children (156 children born to mothers with hyperandrogenism and 1060 born to normal mother) were followed up their glycometabolism in mean age of 5years. Imprinting genes of oocyte from mothers and lymphocytes from children were examined. A pregestational hyperandrogenism rat model was also established. Findings Children born to women with hyperandrogenism showed increased serum fasting glucose and insulin levels, and were more prone to prediabetes (adjusted RR: 3.98 (95%CI 1.16–13.58)). Oocytes from women with hyperandrogenism showed increased insulin-like growth factor 2 (IGF2) expression. Lymphocytes from their children also showed increased IGF2 expression and decreased IGF2 methylation. Treatment of human oocytes with dihydrotestosterone upregulated IGF2 and downregulated DNMT3a levels. In rat, pregestational hyperandrogenism induced diabetic phenotypes and impaired insulin secretion in offspring. In consistent with the findings in human, hyperandrogenism also increased Igf2 expression and decreased DNMT3a in rat oocytes. Importantly, the same altered methylation signatures of Igf2 were identified in the offspring pancreatic islets. Interpretation Pregestational hyperandrogenism may predispose offspring to glucose metabolism disorder via epigenetic oocyte inheritance. Clinical trial registry no.: ChiCTR-OCC-14004537; www.chictr.org.

The present study compared the therapeutic effects of great curvature plication with duodenal-jejunal bypass (GCP-DJB) and the commonly used sleeve gastrectomy (SG) in rats with type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: Control group (n = 6), SG group (n = 6), and GCP-DJB group (n = 6). Body weight, daily food intake, fasting blood glucose level, fasting insulin level, insulin resistance index, and fasting serum concentrations of glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), and bile acid were measured. In addition, postoperative changes in body weight and daily food intake at 2, 4, 6, 8, 10, and 12 weeks were also recorded. At week 12, an oral glucose tolerance test (OGTT) and insulin release test were performed to determine glucose tolerance. The insulin resistance index (IRI) was also measured. The postprandial secretion curves and area under the curve (AUC) of GLP-1, gastric inhibitory polypeptide (GIP), PYY, and bile acid were also calculated. Before surgery, no significant differences in body weight, daily food intake, fasting blood glucose, fasting insulin, insulin resistance index, fasting GLP-1, PYY, and bile acid were found among the three groups (P > 0.05). At postoperative week 12, body weight and food intake in the SG and GCP-DJB groups were lower than those in the Control group (P

Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear. The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism. GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet. RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM.

The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.

The purpose of this study is to investigate the impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the level of fasting and postprandial serum glucagon-like peptide-1 (GLP-1) in type 2 diabetic mellitus rats. Randomized block design, factorial experiment. Forty-five type 2 diabetic rats were divided into four groups: sham operation (S, n = 10) and sham operation with the hepatic branch of the vagotomy (SV, n = 11), Roux-en-Y gastric bypass (RYGB, n = 12) and RYGB without preservation of the vagus (RYGBV, n = 12). Levels of fasting and postprandial serum GLP-1 30 min after 50 % glucose solution (2 g/kg) by gavage were determined before surgery and postoperatively at 1, 4, and 8 weeks. Interactions between RYGB and the common hepatic branch were also assessed. Roux-en-Y gastric bypass surgery significantly increased the concentration of postprandial serum GLP-1 and maintained it at a higher level (P 0.05). Both RYGB and vagotomy of the hepatic branch had no influence on fasting serum GLP-1 (P > 0.05). During RYGB surgery for the long-term treatment of T2DM, preservation of the hepatic branch of the vagus might have no impact on serum GLP-1 level.

The cardiovascular dysfunction in children born with assisted reproductive technologies has been of great concern. However, the association of ovarian hyperstimulation syndrome (OHSS), a complication of assisted reproductive technologies, with worse cardiovascular functions and underlying mechanism remains unknown.The objective of the study was to assess the cardiovascular functions of children born to mothers with OHSS and investigate the underlying regulator(s).This was a retrospective cohort recruited in a university hospital.We assessed the cardiovascular functions by Doppler echography in 42 children born to OHSS women, 34 children of mothers with non-OHSS in vitro fertilization, and 48 spontaneously conceived (SC) children (mean age ∼ 4.5 y). Groups were matched for gestational age at delivery and birth weight. An isobaric tag for relative and absolute quantitation-labeled proteomics analysis was performed with another set of umbilical arteries from OHSS and SC pregnancies (n = 3 for both groups).Children of OHSS mothers showed a significantly decreased mitral ratio of early to late mitral peak velocities, reduced systolic and diastolic diameters of common carotid arteries, and impaired flow-mediated dilation compared with non-OHSS in vitro fertilization and SC children. Intima-media thickness and arterial stiffness indices were similar in the three groups. In the proteomics study, 1640 proteins were identified from OHSS and SC umbilical arteries, and 40 differentially expressed proteins were selected for further analysis. Estradiol and progesterone were identified as activated upstream regulators.Children born to ovarian-hyperstimulated women displayed cardiovascular dysfunctions. The underlying mechanisms may involve the effects of supraphysiological estradiol and progesterone levels.

Objective To examine epithelial Na + channel (ENaC) expression in endometrium of overweight/obese women with polycystic ovary syndrome (PCOS) during the window of implantation, and to explore the mechanism linking leptin-mediated reduction of γ-ENaC to low endometrial receptivity. Design Controlled, prospective, clinical, experimental study. Setting University-based infertility center. Patient(s) Blood and endometrium samples were collected from 12 control women and 12 overweight/obese PCOS patients. Pregnancy outcomes were obtained from 245 women with male-factor infertility (533 cycles) and 57 infertile women with PCOS (120 cycles) who underwent intrauterine insemination. Intervention(s) Human endometrial biopsies. Main Outcome Measure(s) Expression of ENaC mRNA and protein in endometrium. Result(s) The expression of γ-ENaC decreased in the secretory phase endometrium of PCOS patients who showed increased serum leptin levels. In cultured endometrial cells (Ishikawa cells), leptin dose-dependently down-regulated the expression of γ-ENaC and reduced the JAr spheroid attachment rate, which could be blocked by knockdown of STAT3, a signal in the pathway of leptin receptor activation. The overweight/obese PCOS patients with increased serum leptin levels showed a significantly increased biochemical pregnancy rate, suggesting that high leptin might attenuate endometrial receptivity and increase very early pregnancy loss. Conclusion(s) High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating γ-ENaC expression in the endometrium. These results provide valuable new insights into the molecular mechanisms linking abnormal ENaC gene expression to early pregnancy loss in overweight/obese PCOS patients.

The impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the hypoglycemic effect and glucagon-like peptide-1 (GLP-1) in rats with type 2 diabetes mellitus (T2DM) was investigated, and interactions were preliminarily analyzed.A total of 45 rats with T2DM were divided into four groups: sham operation (S, n = 10), sham operation with the hepatic branch of the vagus resected (SV, n = 11), RYGB (n = 12), and RYGB without preservation of the vagus (RYGBV, n = 12). Body mass, fasting blood glucose (FBG), fasting serum insulin, and concentrations of fasting serum GLP-1 were examined in the first, second, fourth, and eighth week before and after surgery. The effects of RYGB and the hepatic branch of the vagus on GLP-1 levels in the eighth postoperative week were also analyzed.RYGB caused a significant reduction in the weight of rats with T2DM (P 0.05), improved the levels of serum GLP-1 and insulin (P 0.05), and decreased FBG level (P 0.05). Retention of the hepatic branch of the vagus maintained weight reduction for a longer period (P 0.05) and increased the levels of serum GLP-1 and insulin (P 0.05), but had no impact on FBG level (P 0.05).RYGB had better therapeutic efficacy in rats with T2DM. Care should be taken during RYGB surgery to preserve the hepatic branch of the vagus.