Role of CREB/CRTC pathway in maintaining energy homeostasis

Food deprivation is a common stress condition in nature. The mechanisms of fasting responses are well conserved from Drosophila to mammals. Fasting in mammals promotes increases in circulating glucagon and decreases in circulating insulin, that stimulate gluconeogenesis and lipolysis, thereby allowing a transition from glucose to lipid burning as the primary source of energy. The transcription factors, cAMP response element-binding protein (CREB), the cAMP-regulated transcriptional coactivator (CRTC) and Forkhead Box subfamily O transcription factor (FOXO) contribute to stimulation of gluconeogenesis in response to fasting. Earlier studies showed that neuronal CRTC is necessary for starvation resistance. Fasting triggers CRTC nuclear translocation, whereas refeeding inhibits CRTC activity by activating salt-inducible kinases (SIKs). However, the relevant genes that are activated by CRTC in response to fasting are not well-known. In this study, I identified CRTC-dependent fasting-responsive genes and found potential roles for CRTC in modulating one-carbon metabolic pathway and insulin signaling. I found activation of CRTC without fasting treatment is sufficient to induce the expression of some target genes. Besides characterizing roles of CRTC in response to fasting, I also characterized potential roles of CRTC in the fed state. A whole-genome promoter analysis reveals that nearly 15% of the fly genes are putative CREB targets; gene ontology enrichment analysis with these putative targets showed enrichment of multiple developmental processes. Together, these results suggest that CRTC regulates a subset of fasting-responsive genes and engages in crosstalk with multiple signaling pathways to maintain energy homeostasis. CRTC also functions in other physiological processes beyond gluconeogenesis. These studies provide insight into the mechanism by which a fasting-inducible coactivator promotes energy balance