Role of unique miRNAs in development of obesity and type 2 diabetes

Abstract

Obesity is a result of increased energy intake and/or decreased energy expenditure. This energy imbalance varies in different individuals; certain people gain weight more rapidly than others when subjected to similar high calorie diet. However, the etiology and mechanistic insight into these variations are poorly understood. Studying this phenotype in humans is complicated due to variation in diet, physical activity, etc. Therefore, we developed diet induced obese (DIO) and diet resistance (DR) mice to investigate the phenomenon of variable weight gain in response to a high fat diet. C57BL/6J mice were fed high fat diet and bred for multiple generations to derive pure DIO and DR colonies. The DIO and DR mice had similar body weight at birth, but responded differently to HFD (i.e. DIO gained more weight than DR), despite ingesting similar caloric intake. We next inquired the mechanistic reasons for this phenotypic difference. Interestingly, we observed that the body temperature was significantly increased in DR mice, compared to the DIO mice. Consistent with this, we observed increased BAT, muscle and mitochondria specific genes and decreased WAT specific genes in the white adipose tissue (WAT) of DR mice. Considering these mice are genetically similar, we hypothesized that epigenetic modification, such as miRNAs, may play a role in the phenotype diversity. miRNAs are small oligonucleotides that regulate gene expression at the transcriptional and translation levels. We thus profiled expression levels of miRNAs in the WAT of DIO and DR mice. Interestingly, we observed that 17 miRNAs were upregulated, 8 miRNAs were down regulated, while few miRNAs were switched on or off depending on whether the WAT was derived from DIO or DR mice. These data suggest that miRNAs are differentially expressed in the context of adiposity. Further work is in progress to understand the molecular targets of these miRNAs and to definitively ascertain whether change in miRNA expression is an early and causative event in the pathogenesis of obesity