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Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD int

Objectives: Growing evidence shows detrimental effects of paternal obesity on subsequent generations. We designed a micronutrient supplement whose components participate in one carbon metabolism and are anticipated to improve antioxidant capacity. Here, we studied the effects of the supplement on metabolic health and hepatic lipid metabolism in male rats consuming either a normal healthy diet or an obesogenic diet. Methods: Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (CD) or high fat diet (HFD) with or without added micronutrient supplement (CDS; HFDS). After 12 weeks of diet, body composition was measured by magnetic resonance imaging, and blood samples were collected to assess supplementation levels. After 19 weeks of diet, oral glucose tolerance test (OGTT) was performed and plasma was collected to determine insulin release. At 27 weeks of diet, the rats were fasted and culled to harvest blood and tissues. Liver lipids and expression of genes involved in hepatic development and lipid metabolism were measured. Results: Supplementation was confirmed by determining plasma folate concentrations (one component of supplement), which were increased by 26% across supplemented groups. HFD increased adiposity (P < 0.001) and body weight (P < 0.001), both of which were normalized in the HFDS group. HFD fed animals were glucose intolerant (blood glucose during OGTT, P = 0.005) compared to CD fed animals and had to release more insulin to clear an equivalent glucose load (insulin release during OGTT, P < 0.001). In comparison, the animals consuming HFDS needed less insulin to clear an equivalent glucose load (P < 0.001 vs HFD). HFD rats had larger livers than HFDS rats (P < 0.001). Micronutrient supplementation reduced hepatic triglyceride accumulation (P < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Conclusions: Dietary micronutrient supplementation prevented weight gain and adiposity, impr

Objectives: Emerging evidence suggests that paternal obesity plays a significant role on offspring health. Our previous work in rodents showed that high fat diet (HFD) induced paternal obesity reduced offspring glucose tolerance. It has also been reported that paternal obesity can initiate metabolic disturbance in subsequent generations. Therefore, we designed a novel micronutrient supplement to ameliorate the transgenerational effects of paternal obesity. Methods: Founder (F0) male Sprague Dawley rats (3 weeks, 12 per group) were weaned on control (CD) or HFD or diets containing micronutrient supplement (CS; HS), after which they were mated with CD fed females at 19 weeks of age. Twelve F1 offspring from each litter across the four diet groups were weaned on day 21 onto CD, generating four F1 groups. After 14 weeks on CD, they were mated with CD fed females. Male F2 siblings were fed CD or HFD from day 21. After 6 weeks on diet, they underwent EchoMRI (See attached study design). Results: HFD increased adiposity (CD: 12.3%, HFD: 18.6%) in F0 which was normalized by supplementation (HS: 11.7%). Though no paternal effect on adiposity was found in F1 males across the four groups, supplementing F0 had significant impact on F2 body composition (fat mass, fat and lean percentage) without influencing body weight and lean mass after 6 weeks on diet.In F2, post weaning HFD significantly increased fat mass in rats from CD and HFD fed founders (CH vs CC P = 0.0001; HH vs HC P = 0.009) but this effect was significantly reduced by F0 supplementation irrespective of F0 diets (CSH vs CH P = 0.017; and HSH vs HH P = 0.04) [3-way ANOVA][See attached table].Moreover, lean percentage was decreased by post weaning HFD in rats from both non-supplemented F0 diet groups but interestingly this effect was significantly reduced only in rats sired by supplemented CD fed F0 (CSH > CH; P = 0.04). Conclusions: Supplementing CD fed grandfathers ameliorated the deleterious effect of HFD, decreasi

© 2017 The Author(s). Unhealthy diets, and ensuing weight gain, predispose individuals to the development of esophageal adenocarcinoma. We examined the effect of chronic high fat diet (HFD) on the esophageal microbiota of Sprague Dawley rats using Illumina MiSeq amplicon sequencing (V4, 515 F/806 R) and on esophageal expression of IL18, PTGS2, PPARA, FFAR3, and CRAT. The relationships among metabolic parameters, esophageal microbiota, and host gene expression were determined. We observed a significant difference between the upper and lower esophageal microbiota in control fed rats, emphasized by enrichment of Lactobacillus species in the lower esophagus. Rats on HFD gained significantly more fat and had reduced insulin sensitivity. Diet type significantly affected the esophageal microbiota, with Clostridium sensu stricto being enriched in both upper and lower segments of HFD fed rats. Of interest, bacterial pathways related to carotenoid biosynthesis were significantly decreased in the lower esophagus of HFD fed rats. We observed strong correlations between metabolic parameters, the esophageal microbial profiles, and host esophageal gene expression. In particular, Fusobacterium, Rothia, and Granulicatella showed consistent correlations across a range of metabolic and gene markers. Our data indicates that unhealthy diets can significantly alter the esophageal microbiota, and enrich for bacterial species previously associated with chronic gastrointestinal diseases.

Along with diabetes and obesity, chronic kidney disease (CKD) is increasing across the globe. Although some data support an effect of maternal obesity on offspring kidney, the impact of paternal obesity is unknown; thus, we have studied the effect of paternal obesity prior to conception. Male Sprague Dawley rats were fed chow diet or high fat diet (HFD) for 13-14 weeks before mating with chow-fed females. Male offspring were weaned onto chow and killed at 27 weeks for renal gene expression and histology. Fathers on HFD were 30% heavier than Controls at mating. At 27 weeks of age offspring of obese fathers weighed 10% less; kidney triglyceride content was significantly increased (5.35 ± 0.84 vs. 2.99 ± 0.47 μg/mg, p < 0.05, n = 8 litters per group. Histological analysis of the kidney demonstrated signs of tubule damage, with significantly greater loss of brush border, and increased cell sloughing in offspring of obese compared to Control fathers. Acat1, involved in entry of fatty acid for beta-oxidation, was significantly upregulated, possibly to counteract increased triglyceride storage. However other genes involved in lipid metabolism, inflammation and kidney injury showed no changes. Paternal obesity was associated with renal triglyceride accumulation and histological changes in tubules, suggesting a mild renal insult in offspring, who may be at risk of developing CKD.

There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One of the more important questions in this research area is: do changes in sperm DNA methylation have phenotypic consequences for offspring? We have previously reported that offspring of obese male rats have altered glucose metabolism compared with controls and that this effect was inherited through nongenetic means. Here, we describe investigations into sperm DNA methylation in a new cohort using the same protocol. Male rats on a high-fat diet were 30% heavier than control-fed males at the time of mating (16-19 weeks old, n = 14/14). A small (0.25%) increase in total 5-methyl-2-deoxycytidine was detected in obese rat spermatozoa by liquid chromatography tandem mass spectrometry. Examination of the repetitive fraction of the genome with methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) and pyrosequencing revealed that retrotransposon DNA methylation states in spermatozoa were not affected by obesity, but methylation at satellite repeats throughout the genome was increased. However, examination of muscle, liver, and spermatozoa from male 27-week-old offspring from obese and control fathers (both groups from n = 8 fathers) revealed that normal DNA methylation levels were restored during offspring development. Furthermore, no changes were found in three genomic imprints in obese rat spermatozoa. Our findings have implications for transgenerational epigenetic reprogramming. They suggest that postfertilization mechanisms exist for normalising some environmentally-induced DNA methylation changes in sperm cells.

The gut microbiota is emerging as a new factor in the development of obesity. Many studies have described changes in microbiota composition in response to obesity and high fat diet (HFD) at the phylum level. In this study we used 16s RNA high throughput sequencing on faecal samples from rats chronically fed HFD or control chow (n = 10 per group, 16 weeks) to investigate changes in gut microbiota composition at the species level. 53.17% dissimilarity between groups was observed at the species level. Lactobacillus intestinalis dominated the microbiota in rats under the chow diet. However this species was considerably less abundant in rats fed HFD (P<0.0001), this being compensated by an increase in abundance of propionate/acetate producing species. To further understand the influence of these species on the development of the obese phenotype, we correlated their abundance with metabolic parameters associated with obesity. Of the taxa contributing the most to dissimilarity between groups, 10 presented significant correlations with at least one of the tested parameters, three of them correlated positively with all metabolic parameters: Phascolarctobacterium, Proteus mirabilis and Veillonellaceae, all propionate/acetate producers. Lactobacillus intestinalis was the only species whose abundance was negatively correlated with change in body weight and fat mass. This species decreased drastically in response to HFD, favouring propionate/acetate producing bacterial species whose abundance was strongly correlated with adiposity and deterioration of metabolic factors. Our observations suggest that these species may play a key role in the development of obesity in response to a HFD.