Deciphering Modes of Action of Obesogens; Nuclear Receptor Mediated Metabolic Disruption

Obesity remains a leading health condition worldwide, with increasing prevalence in adults and in children. The causes for obesity are multifactorial; however, one suggested cause is exposure to obesogens, which are compounds that affect metabolic endpoints. Obesogens are known to be ligands for members of the nuclear receptor family. Examples of obesogens are bisphenol A (BPA) and diethylstilbestrol (DES) acting on the estrogen receptors, and rosiglitazone and tetrabromobisphenol A (TBBPA) acting on PPAR. In addition, ligands for LXR are also known to alter metabolic endpoints. The aim of the current study is to investigate whether ligands for ERs, PPAR and LXR affect lipid metabolism in zebrafish acting through similar downstream pathways and whether they induce adipogeneis. We analyzed whole organism mRNA expression in zebrafish treated with different nuclear receptor ligands by RNA sequencing, and identified that 1114 genes were regulated in common. We also identified a common pathway and common set of genes related to metabolism that is altered by these different ligands. To investigate the potential obesogenic effect of these ligands, we treated zebrafish larvae with the ligands in combination with a high fat diet and visualized lipid accumulation by Oil Red O staining. We propose that different obesogens acting through different nuclear receptors affect a common set of genes and pathways that alters the metabolism. Another section of my thesis focuses on the construction of an inexpensive, convenient and portable device that fits any microscope stage top and is used to control the temperature in imaging samples over extended periods of time. This thermocontrol plate, can be used for live cell imaging over long duration of time and live monitoring and studying of progression of development of small animals, requiring constant temperature. This plate replaces the need for an expensive microscope incubator that is mounted on the microscope, or a heated stage. The thermocontrol plate has a hollow structure built by the technology of 3D printing, and it contains metallic thermal beads that are heated by a probe. It is easy to use, stably controls the temperature, is reusable and inexpensive. It works well on any inverted microscope.