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Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals (NimbleGen expression)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: yanchang wei

PROVIDER: E-GEOD-43187 | 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 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.

Project description:Maternal low-protein diet increases the susceptibility of offspring to type 2 diabetes. An insult to the pancreas during development can have long-term consequences on ?-cell mass and function. Because nutrients and growth factors signaling converge on mTOR, we hypothesized that mTOR plays a central role in ?-cell programming during fetal development. In this study, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, ?-cell fraction, and mTOR signaling. Adult LP0.5 offspring demonstrated enhanced insulin sensitivity but remained glucose intolerant due to an insulin secretory defect and not reduced ?-cell mass. The insulin secretory defect was distal to Ca2+ influx, at the level of proinsulin biosynthesis and insulin content. LP0.5 islets exhibited reduced mTOR protein and increased expression of specific microRNAs. The reductions in mTOR protein and insulin secretion in LP0.5 islets were restored to normal by blockade of microRNAs 199a-3p and 342. Finally, transient activation of mTORC1 signaling in ?-cells during the last week of pregnancy rescued the neonatal ?-cell fraction defect and metabolic abnormalities in LP0.5 mice. These findings identify a major role of microRNAs and mTOR in ?-cell programing by maternal low-protein diet. To investigate which microRNAs are altered in islets isolated from 2-3 months old male offspring of dams fed low-protein diet (LP0.5) or control diet throughout pregnancy Pancreatic islets were isolated from 2-3 months old male offspring of dams fed low-protein diet (LP0.5) or control diet throughout pregnancy. Islets were isolated by collagenase digestion. The pancreas was perfused via the common duct with 1 mg/ml collagenase XI (Sigma-Aldrich) in HBSS (Life Technologies). Pancreatic digestion was carried out at 37 °C for 15 min, after which cold HBSS with 2.5% FBS (Life Technologies) was added. The suspension was centrifuged at 1000 rpm for 30s, washed 3 times with HBSS with 2.5% FBS, resuspended in RPMI complete media (RPMI 1640 with 5 mM Glucose, 10% FBS,100 IU/ml penicillin, 100 g/ml streptomycin) and poured onto a 70 µm cell strainer (BD Falcon, BD Biosciences). Islets were rinsed and handpicked. Islets were allowed to recover overnight in RPMI complete media before RNA isolation using MirVana Kit (Life Technologies).

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Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals (NimbleGen expression)

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