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Effects of dietary obesity in fathers on gene expression of fat in the female offspring (mRNA data)

ABSTRACT: The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed M-NM-2-cell M-bM-^@M-^XdysfunctionM-bM-^@M-^Y in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet altered the expression of 211 pancreatic islet genes in adult female offspring (P < 0.001); genes belonged to 8 functional clusters, including calcium ion binding, primary metabolic processes and ATP binding, and organ/system development. Broader KEGG pathway analysis of 2014 genes differentially expressed at the P < 0.01 level further demonstrated involvement of insulin and calcium signaling, and MAPK pathways. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies. F0 founders were male Sprague Dawley rats, divided into two groups: high fat (HF) and control. The HF fathers were given commercially prepared high-fat pellets (43% as fat), while the controls ate standard laboratory chow (9% as fat). The two groups of fathers had distinct phenotypes; the HF fathers were significantly heavier with increased adiposity, and they were also glucose intolerant and insulin resistant. At 15 weeks of age, fathers were mated with normal females consuming chow to generate the F1 offspring. Only female offspring were studied. Female offspring were weaned unto standard laboratory chow at 3 weeks. At 6 and 12 weeks, an intraperitoneal glucose tolerance test (IpGTT) was performed to measure blood glucose and insulin profile; at 11 weeks, an intraperitoneal insulin tolerance test was done. The body weight and adiposity of these offspring were not different between the two groups. The HF offspring had glucose intolerance and impaired glucose-induced insulin response, mainly at the acute phase, observed since 6 weeks. The IpITT was not different between groups. At 14 weeks, fat was harvested from the two groups of offspring.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Margaret Morris

PROVIDER: E-GEOD-33551 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed Î²-cell âdysfunctionâ in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet was observed to alter gene expression of pancreatic islet genes in adult female offspring (P < 0.001); affected functional clusters includes calcium ion binding, insulin, apoptosis, Wnt and cell cycle organ/system development. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies. F0 founders were male Sprague Dawley rats, divided into two groups, high fat (HF) and control. The HF fathers were given commercially prepared high-fat pellets (43% as fat); while the controls ate standard laboratory chow (9% as fat). The two groups of fathers had distinct phenotype; the HF fathers were significantly heavier with increased adiposity, they were also glucose intolerant and insulin resistant. At 15 weeks of age, fathers were mated with normal females consuming chow, to generate the F1 offspring. Only female offspring were studied. Female offspring were weaned unto standard laboratory chow at 3 weeks. At 6 and 12 weeks, intraperitoneal glucose tolerance test (IpGTT) was performed to measure blood glucose and insulin profile; at 11 weeks, intraperitoneal insulin tolerance test was done. The body weight and adiposity of these offspring were not different between the two groups. The HF offspring had glucose intolerance and impaired glucose-induced insulin response, mainly at the acute phase, observed since 6 weeks. The IpITT was not different between groups. At 13 weeks, islets were harvested from the two groups of offspring.

Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.

Project description:Slimming is globally prevalent especially in young women, and it may contribute to the metabolic health of their offspring. Whereas some Lamarckian ideas about environmental inheritance have been dismissed, increasing evidence suggest that certain acquired traits can be transmitted to the next generation. It is therefore of great interest to determine how and to what extent a maternal lifestyle change contributes to their offspring. Here we show that enriched environment (EE) induced maternal slimming improves general health and reprograms metabolic gene expression in mice offspring. EE in mothers induced decreased body weight, adiposity, and improved glucose tolerance and insulin sensitivity. Relative to controls, their offspring exhibited improved general health such as reduced fat accumulation, enhanced metabolic parameters as well as glucose tolerance and insulin sensitivity. Maternal slimming altered the expression of 1,732 genes in the liver of offspring, with coherent downregulation of genes involved in lipid and cholesterol biosynthesis. Epigenomic profiling in offspring revealed numerous changes in cytosine methylation depending on maternal slimming, including hypermethylation of several genes involved in lipid biosynthesis, correlated with the downregulation of these genes. Maternal slimming also altered overall transcriptome patterns in mature oocytes, which contributes largely to the metabolic health and gene expression patterns in offspring. Overall, our studies suggest that maternal slimming have a beneficial role in regulating metabolic profiles in offspring, implying that it might be considered as a potential strategy to reverse the global prevalence of obesity and related metabolic syndromes. Female F0 founders were raised on a standard diet in a normal cage until 12 weeks of age, at which point they were placed into the enriched environmental cage or stayed in the normal cage (chosen at random) for 4 weeks. Males were always raised on a standard diet in the standard cage. At 16 weeks, female F0 founders were mated with males in standard conditions. After 1 or 2 days, males were removed, and pregnant females were left alone with a standard diet in the standard cage until their litters were 3 weeks of age. Note that we always used virgin males to avoid confounding effects brought about by the males. Moreover, males mated with two female groups did not differ in phenotypic data (body weight, adiposity, fasting blood glucose and insulin levels). At 3 weeks of age, partial offspring were sacrificed and the median lobe of liver was rapidly dissected out and flash-frozen in liquid N2, each from an independent mother. Samples from five control and four slimming offspring, each from different mothers, were chosen for microarray analysis.

Project description:We studied the effect of dietary fat type, varying in polyunsaturated/saturated fatty acid ratio's (P/S) on development of metabolic syndrome. C57Bl/6J mice were fed purified high-fat diets (45E% fat) containing palm oil (HF-PO; P/S 0.4), olive oil (HF-OO; P/S 1.1) or safflower oil (HF-SO; P/S 7.8) for 8 weeks. A low-fat palm oil diet (LF-PO; 10E% fat) was used as a reference. Additionally, we analyzed diet-induced changes in gut microbiota composition and mucosal gene expression. The HF-PO diet induced a higher body weight gain and liver triglyceride content compared to the HF-OO, HF-SO or LF-PO diet. In the intestine, the HF-PO diet reduced microbial diversity and increased the Firmicutes/Bacteroidetes ratio. Although this fits a typical obesity profile, our data clearly indicate that an overflow of the HF-PO diet to the distal intestine, rather than obesity itself, is the main trigger for these gut microbiota changes. A HF-PO diet-induced elevation of lipid metabolism-related genes in the distal small intestine confirmed the overflow of palm oil to the distal intestine. Some of these lipid metabolism-related genes were previously already associated with the metabolic syndrome. In conclusion, our data indicate that saturated fat (HF-PO) has a more stimulatory effect on weight gain and hepatic lipid accumulation than unsaturated fat (HF-OO and HF-SO). The overflow of fat to the distal intestine on the HF-PO diet induced changes in gut microbiota composition and mucosal gene expression. We speculate that both are directly or indirectly contributive to the saturated fat-induced development of obesity and hepatic steatosis. Keywords: Diet intervention study Nine-week-old C57Bl/6J mice were fed a low-fat diet (LF-PO) and three different types of high-fat diet, based on palm oil (HF-PO; P/S1.0), olive oil (HF-OO; P/S4.6) and safflower oil (HF-SO; P/S10.1) for 8 weeks. Body weight was recorded weekly and after 7 weeks of diet intervention an oral glucose tolerance test was performed. After 2 weeks of diet intervention, 6 mice per high-fat diet group were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%) and the small intestines were excised. Adhering fat and pancreatic tissue were carefully removed. The small intestines were divided in three equal parts along the proximal to distal axis (SI 1, SI 2 and SI 3) and microarray analysis was performed on mucosal scrapings.

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Effects of dietary obesity in fathers on gene expression of fat in the female offspring (mRNA data)

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