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

超重和肥胖是许多慢性疾病的危险因素，包括心血管疾病和糖尿病。虽然减肥手术是目前实现显著减肥的黄金标准治疗方法，但它是一种具有手术风险的侵入性手术。因此，确定导致肥胖的途径以及开发预防和治疗肥胖的治疗方法具有新的紧迫性。有研究表明，肠道内分泌细胞在食物相关刺激下释放肠道激素，可以被调节以模拟减肥手术。分泌素（SCT）是一种由位于十二指肠和空肠的肠内分泌细胞释放的激素，最近被证明在Roux en Y胃旁路手术后患者中升高。也有报道称，SCT可以触发棕色脂肪细胞组织（BAT）的激活并刺激脂肪分解。我们的目的是了解SCT作为模拟减肥手术的治疗靶点的作用，所涉及的途径及其对BAT的重要性。我们的策略包括在a)人类SCT-金星十二指肠类器官，b)棕色脂肪细胞培养和c)转基因SCT- cre小鼠中进行SCT的研究。我们将采用多方法策略，包括用CRISPR-Cas9和SCT-Cre转基因小鼠修饰胃肠道类器官，并结合最先进的分子表征（RNA测序、活细胞第二信使成像、串联质谱法的肽组学表征、化学遗传学和体内代谢表型）。使用这些方法，我们将解决SCT的生理释放和作用以及增强SCT分泌的代谢后果。这项工作将允许首次详细分析SCT从人类肠内分泌细胞释放，以及SCT调节全身代谢，食物摄入或bat活性的分子途径

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