Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes

肥胖症的增加导致代谢疾病的患病率增加，包括糖尿病、脂肪肝、 心血管疾病等。退伍军人患这些疾病的比例不成比例， 普通民众。此外，肥胖和糖尿病与创伤后压力密切相关 根据最近的研究，这种疾病现在实际上被认为是糖尿病的预测。科学家现在 肥胖本身对健康无害，但正是脂肪组织的功能障碍导致了 疾病健康的脂肪组织适当地储存和释放能量，并分泌内分泌因子， 与周围器官和组织沟通以调节新陈代谢。然而，不健康的脂肪组织 脂肪储存能力有限，当它发炎时，往往会被拉伸到极限，导致 破坏了许多重要的进程。是什么决定了脂肪组织是“健康”还是“不健康”？ 越来越明显的是，脂肪细胞大小的增加与糖尿病有关。脂肪细胞的大小也 与脂肪组织的增生潜能成反比。也就是说，当新的脂肪细胞可以 通过细胞增生，脂肪细胞的大小保持正常;当限制增生发生时，脂肪细胞的大小 膨胀以处理脂质负荷。因此，我们可以得出结论，脂肪细胞增殖的能力是关键， 代谢健康 脂肪细胞来源于间充质干细胞（MSC），多能细胞，也可以成为肌肉， 骨软骨和其他组织类型。这些细胞如何“决定”遵循哪种分化途径？ 虽然一些调节脂肪细胞分化（或脂肪形成）的途径是已知的，但调节脂肪细胞分化（或脂肪形成）的因子是已知的。 调节这些途径并因此决定细胞命运的机制知之甚少。我们发现了一个潜在的 新的脂肪形成信号，即鞘氨醇-1-磷酸（S1 P）。这种分子通过g蛋白发出信号- 偶联受体以引发多种细胞结果。也有受体无关的功能， 1-磷酸鞘氨醇因为我们之前的工作使我们假设这种分子， 合成它的酶，鞘氨醇激酶1（SK 1），可能在脂肪细胞中起作用，我们做了一个成熟的 脂肪细胞特异性SK 1缺失小鼠。我们发现这些动物有一个基本的表型， 代谢综合征，但他们并不肥胖。具体来说，他们有胰岛素抵抗， 瘦素和胰岛素，并显示出非酒精性脂肪肝的迹象。进一步的调查显示 上调这些动物脂肪组织中的成骨和软骨形成途径和信号传导， 支持了它们在脂肪形成中表现出缺陷。我们假设1-磷酸鞘氨醇， 在细胞内或细胞外环境中，参与产生脂肪组织微环境， 促进来源于MSC的脂肪形成前体的脂肪形成。在本提案中，我们提供了数据 支持SK 1和S1 P下调抗脂肪形成信号通路，这是 代谢健康这些研究不仅揭示了如何保持脂肪组织“健康”， 防止代谢疾病，但“硬币的另一面”是，我们也将发现新的机制， 调节骨生成和软骨生成。在脂肪干细胞中刺激这些途径是 目前是再生医学的一个主要焦点。我们要求VA为这些研究提供资金，因为 糖尿病和组织修复是退伍军人群体非常关心的问题，因此这项工作是高度相关的 退伍军人的健康。

The rise in obesity has led to increased prevalence of metabolic disease including diabetes, fatty liver disease, cardiovascular disease, and others. Veterans suffer from these diseases at a disproportional rate relative to the general population. Additionally, obesity and diabetes are strongly linked with post-traumatic stress disorder, which, based on recent research is now actually considered predictive of diabetes. Scientists now posture that obesity per se is not deleterious to health, but it is the dysfunction of adipose tissue that leads to disease. Healthy adipose tissue stores and releases energy appropriately, and secretes endocrine factors that communicate with peripheral organs and tissues to regulate metabolism. However, unhealthy adipose tissue has limited capacity for lipid storage, and is often stretched to that limit, when it becomes inflamed, leading to disruption of many important processes. What determines whether adipose tissue is ‘healthy’ or ‘unhealthy’? It has become increasingly evident that increased adipocyte size is linked with diabetes. Adipocyte size is also inversely proportional to the hyperplastic potential of adipose tissue. That is, when new adipocytes can be made via cell hyperplasia, adipocyte size stays normal; when a limit to hyperplasia occurs, adipocyte size swells to handle the lipid load. Therefore, we might conclude that ability to proliferate adipocytes is key to metabolic health. Adipocytes arise from mesenchymal stem cells (MSCs), pluripotent cells that can also become muscle, bone cartilage, and other tissue types. How do these cells ‘decide’ which differentiation pathway to follow? While some pathways that regulate adipocyte differentiation (or adipogenesis) are known, the factors that regulate these pathways and thus determine cell fate are poorly understood. We have identified a potentially novel adipogenic signal, namely, sphingosine-1-phosphate (S1P). This molecule signals through g protein- coupled receptors to elicit a variety of cell outcomes. There are also receptor-independent functions for sphingosine-1-phosphate. Because our previous work led us to hypothesize that this molecule and therefore the enzyme that synthesizes it, Sphingosine Kinase 1 (SK1), may have a role in adipocytes, we made a mature adipocyte-specific SK1-deletion mouse. We found that these animals have a basal phenotype much like metabolic syndrome, but they are not obese. Specifically, they are insulin resistant, have high circulating levels of leptin and insulin, and show signs of non-alcoholic fatty liver disease. Further investigation revealed upregulation of osteo- and chondrogenic pathways and signaling in adipose tissue of these animals, which supports that they exhibit a defect in adipogenesis. We hypothesize that sphingosine-1-phosphate, intracellularly or in the extracellular milieu, participates in creating the adipose tissue microenvironment to promote adipogenesis in adipogenic precursors deriving from MSCs. In this proposal we present data supporting that SK1 and S1P downregulate anti-adipogenic signaling pathways, and that this is required for metabolic health. These studies will not only shed light on how to keep adipose tissue ‘healthy’ and therefore protect against metabolic disease, but the ‘flip side of the coin’ is that we will also discover new mechanisms regulating osteogenesis and chondrogenesis. Stimulating these pathways in adipose-derived stem cells is currently a major focus for regenerative medicine. We request funding for these studies from the VA, as both diabetes and tissue repair are of great concern for the veteran population and thus this work is highly relevant to veterans’ health.