SCT-TOD: Targeting secretin secretion - new avenues for the treatment of diabetes and obesity

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Overweight and obesity are risk factors for a number of chronic diseases, including cardiovascular diseases and diabetes. Althoughbariatric surgery is currently the gold standard treatment to achieve significant weight loss, it is an invasive procedure carryingsurgical risks. Therefore, the identification of pathways that lead to obesity and the development of treatments to prevent and treatobesity are taking on a new urgency. It has been suggested that enteroendocrine cells which release gut hormones in response tomeal-related stimuli could be modulated to mimic bariatric surgery.Secretin (SCT), a hormone released from enteroendocrine cells located in the duodenum and jejunum, has been recently shown to beelevated in patients after Roux en Y gastric bypass surgery. It has also been reported that SCT could trigger brown adipocyte tissue(BAT) activation and stimulate lipolysis. We aim to understand the role of SCT as a therapeutic target to mimic bariatric surgery, thepathways involved and its importance on BAT. Our strategy involves the study of SCT in a) Human SCT-Venus duodenal organoids, b)brown adipocyte culture and c) transgenic SCT-Cre mice. We will use a multi-approach strategy involving the generation ofgastrointestinal organoids modified with CRISPR-Cas9 and SCT-Cre transgenic mice, combined with state of the art molecularcharacterisation (RNA sequencing, live-cell second messenger imaging, peptidomic characterisation by tandem mass spectrometry,chemogenetics and in vivo metabolic phenotyping). Using these approaches we will address the physiological release and actions ofSCT and the metabolic consequences of enhancing SCT secretion. This work will allow the first detailed analysis of SCT release fromhuman enteroendocrine cells and of the molecular pathways recruited by SCT to modulate whole body metabolism, food intake orBAT activity