Scope: Maternal obesity leads to glucose intolerance in the offspring. Changes in the gut microbiota are being increasingly implicated in the pathogenesis of diabetes. We hypothesized that inulin intervention during gestation and lactation improves glucose metabolism disorders in mouse offspring from high-fat diet (HD)-fed dams. Procedures: Female C57BL mice were fed a control diet or HD for 4 weeks before mating. After mating, pregnant mice were randomly divided into three groups through gestation and lactation: control diet (CD) group, HD group, and HD treated with inulin (HD-inulin) group. At weaning, glucose metabolic status was assessed. Gut microbial DNA from offspring cecal contents was isolated and processed for metagenomic shotgun sequencing, and taxonomic and functional profiling were performed. Results: Offspring from dams in the HD-inulin groups demonstrated reduced fasting blood glucose, decreased blood glucose area under the curve during the oral glucose tolerance test, and reduced fasting serum insulin and HOMA-IR compared to offspring from dams in the HD group. Nineteen differentially abundant bacterial species were identified between the HD-inulin and HD groups. The HD-inulin group displayed significantly greater abundances of Bacteroides_acidifaciens, Eubacterium_sp_CAG_786, Clostridium_sp_CAG_343, and Bifidobacterium_breve species and lower abundances of Oscillibacter_sp_1_3, Ruminococcus_gnavus_CAG_126, and Bacteroides_massiliensis species. Differentially abundant bacterial species among the three groups were involved in 38 metabolic pathways, including several glucose and lipid metabolism pathways. Conclusion: Our results show that early inulin intervention in HD-fed mouse dams moderates offspring glucose metabolism and gut dysbiosis.

Maternal over-nutrition can lead to metabolic disorders in offspring, whereas maternal dietary genistein may have beneficial effects on the metabolic health of offspring. Our objective was to determine whether maternal dietary genistein could attenuate the detrimental effects of a maternal high-fat diet on their offspring's metabolism and to explore the role of the gut microbiota on their offspring's glucose and lipid metabolism. C57BL/6 female mice were fed either a high-fat diet without genistein (HF), high-fat diet with low-dose genistein (0.25 g/kg diet) (HF.LG), high-fat diet with high-dose genistein (0.6 g/kg diet) (HF.HG) or normal control diet (Control) for 3 weeks prior to breeding and throughout gestation and lactation. The female offspring in the HF group had lower birth weights and glucose intolerance and higher serum insulin, triacylglycerol (TG) and total cholesterol (TC) levels at weaning compared with the Control group. Offspring from HF.LG dams had increased birth weight, improved glucose tolerance, and decreased fasting insulin, whereas the serum TG and TC levels were decreased in HF.HG offspring in comparison with HF offspring. The significant enrichment of Bacteroides and Akkermansia in offspring from genistein-fed dams might play vital roles in improving glucose homeostasis and insulin sensitivity, and the significantly increased abundance of Rikenella and Rikenellaceae_RC9_ gut_group in the HF.HG group may be associated with the decreased serum levels of TG and TC. In conclusion, maternal dietary genistein negates the harmful effects of a maternal high-fat diet on glucose and lipid metabolism in female offspring, in which the altered gut microbiota plays crucial roles. The ability of maternal genistein intake to improve offspring metabolism is important since this intervention could fight the transmission of diabetes to subsequent generations.

Bioactive food components have gained growing attention in recent years. Multiple studies demonstrated that genistein had beneficial effects on metabolism. However, the exact mechanism by which genistein improves metabolism remains unclear, especially the central regulation. This study was designed to evaluate whether addition of genistein to the high-fat diet could counter metabolic disorders and whether these alterations were associated with gene expression in hypothalamus. C57BL/6 mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.25 g/kg diet) (HFG) or a normal control diet (CON) for 8 weeks. Body weight was assessed during the study. After 8-week intervention, content of inguinal subcutaneous adipose tissue (SAT), perirenal visceral adipose tissue (VAT) and brown adipose tissue (BAT) were weighed. Glucose tolerance test, the serum levels of insulin and lipid were assessed. The mRNA of browning marker was detected in the white fat. The hypothalamus was collected for whole transcriptome sequencing and reverse transcription quantitative PCR validation. The results demonstrated that mice fed HFG diet had lower body weight and SAT mass, decrease levels of low-density lipoprotein cholesterol and free fatty acids, higher browning marker of Ucp1 and Cidea in WAT and an improvement in glucose tolerance and insulin sensitivity compared with those in HF group. Transcriptome sequencing showed that there were three differentially expressed genes in hypothalamus among the three groups, including Ucn3, Depp, and Stc1, which were significantly correlated with the browning markers in WAT and insulin sensitivity. Thus, regulating gene expressions in hypothalamus is a potential mechanism for genistein improving metabolism and inducing WAT browning, which may provide a novel target for the precaution and treatment of T2DM.

The prevalence of obesity has become a threatening global public health issue. The consequence of obesity is abnormal energy metabolism. Unlike white adipose tissue (WAT), brown adipose tissue (BAT) has a unique role in nonshivering thermogenesis. Lipids and glucose are consumed to maintain energy and metabolic homeostasis in BAT. Recently, accumulating evidence has indicated that exposure to excess maternal energy intake affects energy metabolism in offspring throughout their life. However, whether excess intrauterine energy intake influences BAT metabolism in adulthood is not clear. In this study, mouse dams were exposed to excess energy intake by feeding a high-fat diet (HFD) before and during pregnancy and lactation. The histology of BAT was assessed by hematoxylin and eosin staining. The genome-wide methylation profile of BAT was determined by a DNA methylation array, and specific site DNA methylation was quantitatively analyzed by methylated DNA immunoprecipitation (MeDIP) qPCR. We found that intrauterine exposure to a high-energy diet resulted in blood lipid panel disorders and impaired the BAT structure. Higher methylation levels of genes involved in thermogenesis and fatty acid oxidation (FAO) in BAT, such as Acaa2, Acsl1, and Cox7a1, were found in 16-week-old offspring from mothers fed with HFD. Furthermore, the expression of Acaa2, Acsl1, and Cox7a1 was down-regulated by intrauterine exposure to excess energy intake. In summary, our results reveal that excess maternal energy leads to a long-term disorder of BAT in offspring that involves the activation of DNA methylation of BAT-specific genes involved in fatty acid oxidation and thermogenesis.