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RNA-sequencing analysis of paternal low-protein diet-induced gene expression change in mouse offspring adipocytes

ABSTRACT: Increasing evidence indicates that parental diet affects the metabolism and health of offspring. It is reported that paternal low-protein diet (pLPD) induces glucose intolerance and the expression of genes involved in cholesterol biosynthesis in mouse offspring liver. The aim of the present study was to determine the effect of a pLPD on gene expression in offspring white adipose tissue (WAT), another important tissue for the regulation of metabolism. RNA-seq analysis indicated that pLPD up- and down-regulated 54 and 274 genes, respectively, in offspring WAT,. The mRNA expression of many genes involved in lipogenesis was down-regulated by pLPD feeding, which may contribute to glucose intolerance. The expression of carbohydrate response element-binding protein β (ChREBP-β), an important lipogenic transcription factor, was also significantly lower in the WAT of pLPD offspring, which may have mediated the down-regulation of the lipogenic genes. By contrast, the LPD did not affect the expression of lipogenic genes in the WAT of the male progenitor, but increased the expression of lipid oxidation genes, suggesting that a LPD reduces WAT mass by activating lipid oxidation, and that LPD may reduce WAT mass using differing mechanisms in parents and offspring. These findings add to our understanding of how paternal diet can regulate metabolism in their offspring.

ORGANISM(S): Mus musculus

PROVIDER: GSE121774 | GEO | 2019/07/15

REPOSITORIES: GEO

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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: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 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.

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RNA-sequencing analysis of paternal low-protein diet-induced gene expression change in mouse offspring adipocytes

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