"L-cells in the intestinal epithelium are specialized enteroendocrine cells which secrete several peptide hormones after a meal, including glucagon-like peptide 1 (GLP1), oxyntomodulin (OXM) and peptide tyrosine tyrosine (PYY). These hormones are key regulators of glucose metabolism and body weight, by stimulating insulin release by pancreatic beta cells, slowing down gastric emptying and by acting on brain areas involved in body weight control. Although all three of these hormones are at least in pre-clinical trials for the treatment of obesity and type 2 diabetes mellitus, surprisingly little is known about the biology of L-cells and the molecular mechanisms behind metabolite sensing as well as GLP1/OXM/PYY expression and release by L-cells. This proposal aims to identify novel regulators of L-cell biology by defining transcription factors regulating these processes.Transcription factors are critical regulators of all cellular processes; nonetheless the identification of transcription factors involved in L-cell biology has not been addressed yet in a systematical manner. In the proposed work, the applicant will use a lentiviral-based siRNA knockdown screen to determine which transcription factors are critical for metabolite sensing by L-cells, subsequent GLP1/OXM/PYY expression and release as well as L-cell survival and mitosis in vitro. Finally, post-translational modifications of the defined transcription factors, their target genes and the affected signaling pathways will be characterized. The expected results will allow us to understand how fuel sensing is mechanistically linked to release of these three key peptide hormones by L-cells and thus increase our knowledge of this highly relevant enteroendocrine cell type."