Maternal High-Fat Diet Programs Offspring Liver Steatosis in a Sexually Dimorphic Manner in Association with Changes in Gut Microbial Ecology in Mice.
ABSTRACT: The contributions of maternal diet and obesity in shaping offspring microbiome remain unclear. Here we employed a mouse model of maternal diet-induced obesity via high-fat diet feeding (HFD, 45% fat calories) for 12 wk prior to conception on offspring gut microbial ecology. Male and female offspring were provided access to control or HFD from weaning until 17 wk of age. Maternal HFD-associated programming was sexually dimorphic, with male offspring from HFD dams showing hyper-responsive weight gain to postnatal HFD. Likewise, microbiome analysis of offspring cecal contents showed differences in ?-diversity, ?-diversity and higher Firmicutes in male compared to female mice. Weight gain in offspring was significantly associated with abundance of Lachnospiraceae and Clostridiaceae families and Adlercreutzia, Coprococcus and Lactococcus genera. Sex differences in metagenomic pathways relating to lipid metabolism, bile acid biosynthesis and immune response were also observed. HFD-fed male offspring from HFD dams also showed worse hepatic pathology, increased pro-inflammatory cytokines, altered expression of bile acid regulators (Cyp7a1, Cyp8b1 and Cyp39a1) and serum bile acid concentrations. These findings suggest that maternal HFD alters gut microbiota composition and weight gain of offspring in a sexually dimorphic manner, coincident with fatty liver and a pro-inflammatory state in male offspring.
Project description:Maternal obesity is known to predispose offspring to metabolic and neurodevelopmental abnormalities. While the mechanisms underlying these phenomena are unclear, high fat diets dramatically alter intestinal microbiota, and gut microbiota can impact physiological function. To determine if maternal diet-induced gut dysbiosis can disrupt offspring neurobehavioral function, we transplanted high fat diet- (HFD) or control low fat diet-associated (CD) gut microbiota to conventionally-housed female mice. Recipient mice were then bred and the behavioral phenotype of male and female offspring was tracked. While maternal behavior was unaffected, neonatal offspring from HFD dams vocalized less upon maternal separation than pups from CD dams. Furthermore, weaned male offspring from HFD dams had significant and selective disruptions in exploratory, cognitive, and stereotypical/compulsive behavior compared to male offspring from CD dams; while female offspring from HFD dams had increases in body weight and adiposity. 16S metagenomic analyses confirmed establishment of divergent microbiota in CD and HFD dams, with alterations in diversity and taxonomic distribution throughout pregnancy and lactation. Likewise, significant alterations in gut microbial diversity and distribution were noted in offspring from HFD dams compared to CD dams, and in males compared to females. Regression analyses of behavioral performance against differentially represented taxa suggest that decreased representation of specific members of the Firmicutes phylum predict behavioral decline in male offspring. Collectively, these data establish that high fat diet-induced maternal dysbiosis is sufficient to disrupt behavioral function in murine offspring in a sex-specific manner. Thus these data reinforce the essential link between maternal diet and neurologic programming in offspring and suggest that intestinal dysbiosis could link unhealthy modern diets to the increased prevalence of neurodevelopmental and childhood disorders.
Project description: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.
Project description:Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metabolism. However, it is important to assess whether maternal consumption of a HFD during critical periods of development can lead to metabolic changes in the offspring metabolism. This study evaluated the potential effects of metabolic programming on the impairment of insulin signalling in recently weaned offspring from obese dams. Additionally, we investigated if early exposure to an obesogenic environment could exacerbate the impairment of glucose metabolism in adult life in response to a HFD. Swiss female mice were fed with Standard Chow (SC) or a HFD during gestation and lactation and tissues from male offspring were analysed at d28 and d82. Offspring from obese dams had greater weight gain and higher adiposity and food intake than offspring from control dams. Furthermore, they showed impairment in insulin signalling in central and peripheral tissues, which was associated with the activation of inflammatory pathways. Adipose tissue was ultimately the most affected in adult offspring after HFD rechallenge; this may have contributed to the metabolic deregulation observed. Overall, our results suggest that diet-induced maternal obesity leads to increased susceptibility to obesity and impairment of insulin signalling in offspring in early and late life that cannot be reversed by SC consumption, but can be aggravated by HFD re-exposure.
Project description:SCOPE:We investigated the long-term effects of maternal high-fat consumption and post-weaning exercise on offspring obesity susceptibility and insulin resistance. METHODS:C57BL/6J dams were fed either a high-fat (HFD, 40% kcal fat) or low-fat (LFD, 10% kcal fat) semi-synthetic diet during pregnancy and lactation. After weaning, male offspring of both maternal diet groups (mLFD; mHFD) received a LFD. At week 7, half of the mice got access to a running wheel (+RW) as voluntary exercise training. To induce obesity, all offspring groups (mLFD +/-RW and mHFD +/-RW) received HFD from week 15 until week 25. RESULTS:Compared to mLFD, mHFD offspring were more prone to HFD-induced body fat gain and exhibited an increased liver mass which was not due to increased hepatic triglyceride levels. RW improved the endurance capacity in mLFD, but not in mHFD offspring. Additionally, mHFD offspring +RW exhibited higher plasma insulin levels during glucose tolerance test and an elevated basal pancreatic insulin production compared to mLFD offspring. CONCLUSION:Taken together, maternal HFD reduced offspring responsiveness to the beneficial effects of voluntary exercise training regarding the improvement of endurance capacity, reduction of fat mass gain, and amelioration of HFD-induced insulin resistance.
Project description:<h4>Objective</h4>This study aimed to determine whether maternal high-fat diet (HFD) consumption in nonhuman primates alters the ability of offspring to adapt metabolically to nutrient and caloric challenges.<h4>Methods</h4>Offspring from Japanese macaque dams fed either a control (CTR) diet or HFD were weaned onto a CTR diet creating two groups: maternal HFD (mHFD, n?=?18) and maternal CTR (mCTR) diet (n?=?12). Male and female offspring were exposed to a 5-day 30% calorie restriction and to a 35-day HFD challenge (HFDC), at 16 and 24 months of age, respectively. Caloric intake, body weight, and energy expenditure were measured.<h4>Results</h4>Offspring from both groups showed similar body weight, food intake, and metabolic adaptations to a 5-day calorie restriction. mHFD offspring demonstrated increased food intake and early weight gain in response to a 35-day HFDC; however, group differences in weight dissipated during the challenge. Unlike mCTR animals, the mHFD group had a significant increase in fasting insulin after acute HFD exposure.<h4>Conclusions</h4>The current findings indicate that offspring exposed to an mHFD show metabolic adaptations to calorie restriction that are largely similar to those of offspring exposed to a mCTR diet but show delayed adaptation upon exposure to an acute HFDC.
Project description:The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERB?, CRY, PER) and metabolic (PPAR?, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPAR? mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPAR? transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPAR? transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPAR? expression prior to obesity development.
Project description:Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.
Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.
Project description:OBJECTIVE:Maternal high-fat diet (HFD) may alter the offspring intestinal immune system, thereby enhancing susceptibility toward inflammatory bowel disease. The objective of the current study was to investigate the impact of maternal HFD on offspring intestinal health using a mouse model of dextran sulfate sodium (DSS)-induced colitis. METHODS:Dams were provided with either HFD (60%) or control diet. After weaning, female offspring from both groups were kept on 45% HFD. At 14 weeks of age, offspring were subjected to 2.5% DSS in drinking water for 5 days, followed by 5 days of recovery. RESULTS:Offspring from maternal HFD had higher body weight gain before DSS induction and had higher liver and fat weights with increased adipocyte size at necropsy. When subjected to DSS treatment, HFD offspring had accelerated body weight loss and exaggerated disease activity index. HFD offspring had an elevated histopathological score and interleukin (IL)-1?, IL-6, and IL-17 expression with upregulated NF-?B signaling. Maternal HFD resulted in enhanced neutrophil infiltration associated with elevated expression of monocyte chemoattractant protein-1. Furthermore, maternal HFD suppressed AMP-activated protein kinase activity and decreased sirtuin 1 and p53 protein contents in offspring gut. CONCLUSIONS:Maternal HFD consumption predisposes offspring to a higher susceptibility to develop inflammatory bowel disease.
Project description:The fetal period represents an important window of susceptibility for later obesity and metabolic disease. Maternal vitamin D deficiency (VDD) during pregnancy is a global concern that may have long-lasting consequences on offspring metabolic health. We sought to determine whether a VDD in utero environment affects fetal adipose tissue development and offspring metabolic disease predisposition in adulthood. Furthermore, we sought to explore the extent to which the VDD intrauterine environment interacts with genetic background or postnatal environment to influence metabolic health. Eight-week-old P0 female C57BL/6J mice were fed either a VDD diet or sufficient diet (VDS) from four weeks before pregnancy (periconception) then bred to male Avy/a mice. Females were maintained on the diets throughout gestation. At weaning, Avy/a and a/a male F1 offspring were randomized to low-fat (LFD) or high-fat diet (HFD) until 19 weeks of age, at which point serum and adipose tissue were harvested for analyses. Mice born to VDD dams weighed less at weaning than offspring born to VDS dams but experienced rapid weight gain in the four weeks post weaning, and acquired a greater ratio of perigonadal (PGAT) to subcutaneous (SQAT) than control offspring. Additionally, these mice were more susceptible to HFD-induced adipocyte hypertrophy. Offspring of VDD dams also had greater expression of Pparg transcript. These novel findings demonstrate that in utero VDD, an easily correctable but highly prevalent health concern, predisposes offspring to long-term adipose tissue consequences and possible adverse metabolic health complications.