The Impact of Intrauterine Nutrition and Epigenetic Modifications on the Development of Obesity and Type II Diabetes

Ammad Khan

Introduction.  Nutrition, especially early dietary exposures, plays a critical role in a person’s health throughout their life1.It has been substantiated that external factors can cause cell type-dependent epigenetic changes including those that are commonly attributed to obesity and diabetes2,9,10. Obesity, defined as a BMI greater than 30, has been shown to increase the chances of developing many diseases including diabetes. Type II Diabetes is a condition in which cells develop insulin resistance coupled with pancreatic beta cell deficiency which leads to hyperglycemia. Studies have demonstrated synthetic post-weaning diets in mice resulted in hyper-methylated paternal Insulin Growth Factor-2 allele leading to insulin resistance in offspring5. These studies could suggest which genetic predispositions are more likely to lead to diabetes and obesity can result in more accurate genetic testing. Methods.  Genetically identical mice were mated and it was found that offspring of obese mothers was significantly heavier than offspring of non-obese mothers. These offspring also showed glucose intolerance and insulin resistance after 3 weeks on the diet. Insulin resistance due to altered GLUT4 transport of insulin into cells8. A ChIP assay showed de-acetylation of H3 by recruiting HDAC1 and HDAC48. Maternal obesogenic diet results in impaired adipose tissue insulin signaling in offspring primarily through downregulated IRS-1 regulatory subunits of P13K. Total RNA was extracted from adipose tissue using mirVANA miRNA Isolation Kit and q-PCR was performed on a StepOnePlus Real-Time PCR system5. Results. Offspring of obese mothers and non-obese mothers were compared, both groups were given an obesogenic diet and both resulted in weight gain but offspring of obese mothers became significantly heavier. Using a ChIP assay, it was found that de-acetylation and di-methylation of specific amino acid residues in the N-tail of histone 3 lead to a co-repressor complex formation which interferes with the activation complex leading to reduced glut4 gene transcription8. PCR results showed using 5 different miRNAs it was found that when IRS-1 expression is reduced so is the incidence of obesity and diabetes5. Conclusion.  Obesity and diabetes can be, in part, explained due to genetic changes that are clearly seen in the offspring of obese mothers. Changes in Glut4 transport of glucose and IRS-1 expression in insulin resistance are linked to epigenetic modifications more commonly seen in the offspring of obese mothers. These genetic changes can be used as the basis of testing and ultimately the identification of high risk individuals and ultimately their treatment.

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