Obesity and diabetes are becoming increasingly prevalent worldwide. The long term research goal is to better understand the molecular mechanisms of adipocyte biology and insulin signaling so that these biological processes can be better controlled in humans. The immediate research goal is to examine a putative convergence of nuclear hormone receptor (NHR) and forkhead factor signaling. Specifically, those pathways mediated by PPARgamma, and Foxo1 in mammals and DAF-12 (worm NHR) and DAF-16 (worm forkhead factor) in C. elegans. I have discovered that PPARgamma, interacts directly with Foxo1 and DAF-12 interacts with DAF-16 suggesting NHR-forkhead interactions may be conserved in evolution. Foxo1 antagonizes the transcriptional activation potential of PPARgamma, and vice versa suggesting a reciprocally antagonistic interaction. Finally, Foxo1 antagonizes adipogenesis consistent with an inhibitory effect on the proadipogenic activity of PPARgamma. The central hypothesis is that signaling pathways mediated by NHRs (PPARgamma/DAF-12) and forkhead factors (Foxo1/DAF-16) converge to affect metabolic and developmental processes and that this convergence requires a direct interaction between NHRs and forkhead factors.
Specific Aim #1 is to determine how Foxo1 antagonizes adipogenesis.
Specific Aim #2 is to examine convergence of DAF-12 and DAF-16 signaling in C. elegans.
Specific Aim #3 is to determine if mammalian and worm NHRs and forkhead factors can function interchangeably. The central hypothesis will be tested by establishing correlations between the ability of forkhead factors to interact with NHRs and to mediate biological effects. My goal during this award period is to couple research skills attained in the past (NHRs), present (adipocyte biology and insulin signaling) and future (C. elegans and forkhead factor signaling) to achieve the experimental objectives. The excellent research environment at Johns Hopkins coupled with an extensive collaborative team of experts in relevant fields of study is ideal for successful completion of the proposed work.
| Dowell, Paul; Otto, Tamara C; Adi, Saleh et al. (2003) Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem 278:45485-91 |
