Obesity Suppresses the GUCY2C endocrine Gut-Brain Axis Disrupting Satiety

 描述(申请人提供)：肥胖是一种全球性的流行病，发病率、死亡率和医疗费用的趋势都在加快。治疗效果有限，或者存在安全方面的问题。在这种对更有效、更安全的抗肥胖疗法的临床需求尚未得到满足的背景下，最近发现了一种调节食欲和代谢的新的肠道-大脑内分泌轴，这为推进这种疾病的治疗和预防提供了一个独特的机会。跨膜受体鸟苷环化酶C(GUCY2C)被其同源旁分泌激素尿鸟苷(小肠)和鸟苷(结肠)激活后，被认为是肠上皮细胞动态平衡的关键调节因子。最近发现的GUCY2C在下丘脑的表达和功能，以及循环中的尿鸟苷水平随着热量摄入的增加，将GUCY2C信号延伸到中枢神经系统的内分泌调节回路中，调节饱足感。事实上，这些观察表明了一种生理模型，在这种模型中，摄入食物刺激肠道内分泌的尿鸟苷，尿鸟苷循环到下丘脑，诱导厌食信号。此外，肥胖小鼠餐后尿鸟苷分泌受到抑制，这表明了一种推动肥胖的病理生理机制，但在治疗上是有针对性的。该项目的最终长期目标是阐明下丘脑GUCY2C信号调节饱腹感的机制，以告知GUCY2C配体治疗在治疗和预防肥胖症中的作用。为了实现这一长期目标，提出了三个具体目标。在目标1中，我们将定位GUCY2C在下丘脑中调节食欲的表达。利用独特的ü-半乳糖苷酶GUCY2C报告小鼠，我们将确定表达GUCY2C的下丘脑核、细胞类型和神经元亚型。这些结果将通过原位RNA杂交、免疫印迹、免疫染色和GUCY2C信号分析得到证实。在目标2中，我们将确定下丘脑和肠道GUCY2C在调节食欲中的相对作用。利用我们实验室开发的组织特异性条件性小鼠模型，我们将消除GUCY2C在肠道或脑中的表达，并确定这些治疗对GUCY2C配体诱导的饱腹感的影响，以及对食物消耗和体重的慢性影响。在目标3中，我们将定义将GUCY2C激活与饱足信号联系起来的机制。初步数据表明，GUYC2C配体诱导的饱腹感与下丘脑POMC表达的增加有关，但与其他厌食症或厌食症转录本无关。在这里，我们将展示POMC在连接GUCY2C下丘脑信号与饱腹感和食欲调节中的作用。总之，这些研究将定义一种新的内分泌机制，有助于正常的生理控制食物摄入量。它们代表了必要的证据基础，最终将这一以前未知的肠道-脑轴转化为针对GUCY2C的新治疗方法，以预防和治疗肥胖症和代谢性疾病。

 DESCRIPTION (provided by applicant): Obesity is a global pandemic with accelerating trends in morbidity, mortality, and medical expenditures. Treatments have been limited in efficacy, or burdened with safety concerns. In the context of this unmet clinical need for more effective and safe anti-obesity therapies, the recent discovery of a new gut-brain endocrine axis regulating appetite and metabolism offers a unique opportunity to advance treatment and prevention for this disease. The transmembrane receptor guanylyl cyclase C (GUCY2C) is well characterized as a key regulator of intestinal epithelial homeostasis upon activation by its cognate paracrine hormones uroguanylin (small intestine) and guanylin (colorectum). The recent discovery of GUCY2C expression and function in hypothalamus, along with circulating uroguanylin levels that increase following caloric intake, extends GUCY2C signaling to the central nervous system in an endocrine regulatory circuit mediating satiety. Indeed, these observations suggest a physiological model in which ingestion of food stimulates the endocrine secretion of uroguanylin from intestine, which circulates to hypothalamus to induce anorexigenic signaling. Further, suppressed postprandial uroguanylin secretion in obese mice suggests a pathophysiologic, but therapeutically targetable, mechanism driving obesity. The ultimate, long-term goal of this project is to elucidate mechanisms by which GUCY2C signaling in hypothalamus regulates satiety, to inform the utility of GUCY2C ligand therapy in the treatment and prevention of obesity. To achieve this long-term objective, three specific aims are proposed. In Aim 1, we will map GUCY2C expression regulating appetite in hypothalamus. Leveraging unique ß-galactosidase GUCY2C reporter mice, we will determine the hypothalamic nuclei, cell types, and neuronal subtypes expressing GUCY2C. These results will be confirmed by in situ RNA hybridization, immunoblot, immunostaining and GUCY2C signaling analyses. In Aim 2, we will determine the relative roles of hypothalamic and intestinal GUCY2C in regulating appetite. Using tissue-specific conditional mouse models developed in our laboratory, we will eliminate GUCY2C expression in either intestine or brain and determine the effects of these treatments on GUCY2C ligand-induced satiety, as well as chronic effects on food consumption and body weight. In Aim 3, we will define the mechanisms linking GUCY2C activation to satiety signaling. Preliminary data suggests that GUYC2C ligand-induced satiety is associated with increases in expression of hypothalamic POMC, but not other anorexigenic or orexigenic, transcripts. Here, we will demonstrate the role of POMC in linking GUCY2C hypothalamic signaling with regulation of satiety and appetite. Together, these studies will define a novel endocrine mechanism contributing to the normal physiologic control of food intake. They represent the requisite evidence base to ultimately translate this previously unrecognized gut-brain axis into new therapeutic approaches targeting GUCY2C to prevent and treat obesity and metabolic diseases.