Research Projects

In the last couple of decades, metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular disorders, hypertension, and hypercholesterolemia have become a global health burden. Several epidemiological studies highlighted a critical link between sub-optimal parental nutrition and a higher susceptibility to developing cardiovascular and metabolic disorders in the offspring. Moreover, surmounting evidence documented that parental calorie-excess diets such as high-fat diets (HFD) and high-sugar diets (HSD) lead to a higher susceptibility of their progenies to developing metabolic as well as neurodevelopmental disorders, both early and later in life. Notably, it has been evidenced that diet-induced metabolic dysfunctions can be transmitted to multiple generations of offspring by modulating the epigenome. Of the several model organisms generally employed for transgenerational studies, Drosophila melanogaster stands out as an excellent system by virtue of its short generation time and availability of sophisticated molecular genetic tools. In Drosophila, HFD and HSD perturb metabolic homeostasis by increasing fat storage, ultimately leading to metabolic syndrome and diabetic cardiomyopathy. Moreover, recent studies suggest that these extreme diets may have long-lasting effects over multiple generations. Whole Genome Bisulfite Sequencing (WGBS) indicated globally elevated levels of histone H3 trimethylation (H3K9me3 and H3K27me3) upon acute and ancestral exposure to HSD and HFD as the epigenetic factor responsible for the intergenerational transfer of these traits, and its pharmacological or genetic inhibition rescued the transgenerational defects. Though much has come to light in this field of study, our understanding of the underlying molecular mechanism is largely unclear. The overarching goal of this project is to determine the mechanistic basis by which HSD imparts transgenerational effects on health. Exploiting the strength of Drosophila genetics and available genetic tools, I am keen to decipher how high dietary sugar consumed by adult flies impacts the lipid and carbohydrate metabolism of the larvae they produce. Furthermore, it would be interesting to figure out the additive effect, if any, when both the parents and their progenies are fed on HSD. Apart from these metabolic analyses, WGBS would be performed to map DNA methylation patterns across the entire genome. Extending one step further, we would determine the genetic basis of the signaling cascade/s that connect/s metabolic dysfunction to changes in the epigenetic landscape. Despite some fundamental differences that distinguish human physiology from that of the flies, given the conserved nature of fundamental metabolic processes and signaling pathways, the outcome of our study holds the promise to provide a new directionality in our understanding of the transgenerational effect of high caloric diet.