Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation

摘要 脂肪来源的分泌因子脂联素促进神经酰胺分解代谢增加，这是 依赖于脂联素受体1和2。受体相关神经酰胺酶活性促进神经酰胺 1-磷酸鞘氨醇(S1P)的降解和生成，为细胞提供保护，使其免受Caspase-8- 依赖于支持细胞凋亡的侮辱。神经酰胺向S1P的简单两步转化及其截然相反的作用 这两种脂质对细胞存活和增殖的影响使我们和其他人假设存在一种细胞 由这两种脂类控制的变阻器。由于脂联素促进全身新陈代谢的改善，它 目前尚不清楚脂联素在细胞内的局部作用是否引起了这些保护作用，或者是否 循环代谢环境的改善调节了这些保护性反应。理解这一点 保护机制对于制定策略以维持健康的-细胞种群至关重要 个人。我假设脂联素受体通过调节-细胞的 神经酰胺：S1P比值。在这里，我将评估细胞特异性脂联素受体过表达的影响 或酸性神经酰胺酶(假定为阳性对照)对维持功能性细胞团的作用。此外，我 将研究S1P介导的保护作用对缺乏S1P的小鼠细胞存活的贡献 受体(1、2或3)或过度表达S1P降解酶S1P裂解酶的小鼠。 为了做到这一点，我将利用“Panic-ATTAC”转基因小鼠，它提供了可诱导的， 可滴定，细胞特异性凋亡。因为我通过轻微的细胞凋亡使细胞失活 与坏死相反，我减少了细胞死亡的促炎成分，因此细胞团可以 在停止二聚体处理后重新配制。总体而言，我将能够评估 脂联素、脂联素受体、酸性神经酰胺酶和S1P在A)脂联素介导的抗细胞凋亡中的作用 在细胞中的作用，以及b)脂联素增强功能性细胞再生潜力的能力 质量。我还将确定细胞特异性的脂联素受体1，脂联素受体2， 或酸性神经酰胺酶(AC)足以维持功能性胰岛质量，使用ob/ob小鼠作为模型 糖尿病-细胞衰竭。 这些研究有望为治疗和预防糖尿病提供新的治疗途径。 通过促进细胞功能和促进细胞内的再生过程来促进糖尿病 人口。

Abstract The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2. The receptor-associated ceramidase activity promotes ceramide degradation and generation of sphingosine 1-phosphate (S1P), offering cells protection from caspase-8- dependent pro-apoptotic insults. The simple 2-step conversion of ceramide to S1P and starkly opposing roles of the two lipids on cell survival and proliferation has led us and others to postulate the existence of a cellular rheostat governed by these two lipids. As adiponectin promotes improvements in whole body metabolism, it remains unclear whether the local actions of adiponectin within the cell elicit these protective effects, or if improvements in the circulating metabolic milieu mediate these protective responses. Understanding this protective mechanism is critical for developing strategies to maintain healthy populations of -cells in individuals. I hypothesize that adiponectin receptors promote -cell survival and proliferation by governing the ceramide:S1P ratio. Here, I will evaluate the effects of cell-specific overexpression of adiponectin receptors or acid ceramidase (a presumed positive control) on the maintenance of functional cell mass. Moreover, I will examine the contributions of S1P-mediated protective effects on -cell survival in mice lacking S1P receptors (1, 2 or 3) or mice overexpressing the S1P degrading enzyme S1P lyase. To do that, I will take advantage of the “PANIC-ATTAC” transgenic mouse, which offers inducible, titratable, cell specific apoptosis. Since I functionally inactivate the cells through mild apoptosis as opposed to necrosis, I reduce the pro-inflammatory component of cell death, and thus cell mass can be reconstituted upon cessation of dimerizer treatment. Collectively, I will be able to evaluate the effects of adiponectin, adiponectin receptors, acid ceramidase, and S1P on: a) the adiponectin-mediated anti-apoptotic actions in the -cell, and b) adiponectin's ability to enhance the regenerative potential of functional cell mass. I will also determine if -cell-specific overexpression of adiponectin receptor 1, adiponectin receptor 2, or acid ceramidase (AC) is sufficient to maintain functional islet mass using the ob/ob mouse as a model of diabetic -cell failure. These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of diabetes by promoting -cell functionality, and by promoting regenerative processes within the -cell population.