A systems biology approach for the validation of eQTL in obesity

Abstract

M16 mice are polygenic obese models created by 27 generations of selection for weight gain from an ICR background. Recent transcriptional analysis of adipose and hypothalamus from ~300 M16 × ICR F2 animals identified expression variants (eQTL) and cross‐tissue co‐expression networks of coordinately expressed genes that regulate many processes including satiety, circadian oscillations and stress responses.The purpose of this project is to experimentally validate effects of eQTL and genes in co‐expression networks on obesity phenotypes. Approaches include a Zebrafish screen of morhpholinos, over‐expression and expression knock down by RNAi in adipocyte differentiation, and sequence analysis of regulatory regions. Preliminary results suggest a significant effect of several candidate genes on fat utilization and storage in Zebrafish morpholinos. Sequence analysis of regulatory intervals show variations that alter transcription factor binding sites. These differences may underlie changes in the regulation of gene expression in obese mice. Studies on changes in adipocyte differentiation as a consequence of altered expression levels are just being initiated. Given the biological complexity of fat accretion and energy regulation, a systems biology approach utilizing cumulative statistical and experimental methods may provide needed insight into the molecular basis of obesity.