Thesis (Ph. D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2008.
The ability of an organism to manage energy resources in accordance with its current environmental conditions is critical to its survival. Factors such as nutrient availability and environmental stress must be sensed and integrated to ensure optimized physiological responses. In particular, two evolutionary conserved signaling pathways, the Jun-N-terminal Kinase (JNK) and the Insulin/IGF (IIS) pathways are central regulators of environmental stress and nutritional responses, respectively. These pathways converge at multiple points, allowing organisms to allocate energy appropriately in stress conditions. Recently, studies in both invertebrate and vertebrate model systems have highlighted the importance of system-wide coordination of these processes, with different tissues playing distinct roles and communication among these tissues being critical. Here, I use Drosophila melanogaster to investigate the endocrine mechanisms important in stress and metabolic signaling. First, I characterize the lipocalin NLaz, a secreted molecule that is expressed in the Drosophila fat body in response to active JNK signaling. I show that NLaz acts downstream of JNK to maintain metabolic homeostasis and to promote starvation and stress tolerance. NLaz overexpression also increases hemolymph glucose levels, inhibits growth, and promotes expression of a dFoxo target gene, while NLaz mutants have increased PI3K activity. Together, these results suggest that NLaz promotes survival downstream of JNK through repression of IIS. Second, I show that JNK is essential in the Drosophila insulin producing cells for organism-wide stress responses. Interestingly, I find that environmental stress acts to repress transcription of the secreted insulin like peptide 2, and this repression requires functional JNK. Furthermore, IPC specific inhibition of JNK results in stress sensitivity, a phenotype that is rescued by repression of dilp2. Thus, JNK in the IPC controls organism wide stress tolerance through regulation of dilp2. The work presented in this thesis therefore indicates that two endocrine factors, NLaz and dilp2, are important points of intersection where stress and metabolic signaling converge as part of an adaptive mechanism that balances the needs of the organism with resource availability.