Roles of Sphingolipids in the Pathophysiology of Obesity and Diabetes

鞘脂在肥胖和糖尿病病理生理学中的作用

• 批准号: 9898216
• 负责人: Lauren Ashley Cowart
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898216
• 关键词: Address; Adipocytes; Adipose tissue; Agonist; Animals; Cardiovascular Diseases; Cartilage; Cell Size; Cells; Chondrocytes; Chondrogenesis; Clinical; Coin; Cues; Data; Defect; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Endocrine; Endocrine Glands; Enzymes; Event; Exhibits; Family; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Funding; G-Protein-Coupled Receptors; General Population; Health; Hepatic; Homeostasis; Hormones; Hyperplasia; Hypertrophy; Impairment; Individual; Inflammation; Insulin; Insulin Resistance; Investigation; Leptin; Light; Link; Lipids; Liver diseases; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Organ; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Peripheral; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Posture; Prevalence; Process; Proliferating; Regenerative Medicine; Research; Research Support; Role; SPHK1 enzyme; Scheme; Scientist; Side; Signal Pathway; Signal Repression; Signal Transduction; Signaling Molecule; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stretching; Testing; Tissue Expansion; Tissues; Up-Regulation; Veterans; Visceral; WNT Signaling Pathway; Work; adipocyte differentiation; adipokines; animal tissue; base; bone; cell type; differential expression; extracellular; impaired glucose tolerance; in vivo; lipid biosynthesis; mouse model; non-alcoholic fatty liver disease; novel; receptor; recruit; response; sphingosine 1-phosphate; stem; stem cell differentiation; stem cells; subcutaneous; tissue repair

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.

肥胖的增加导致代谢性疾病的患病率增加，包括糖尿病、脂肪肝、 退伍军人患这些疾病的比例与其他人不成比例。 此外，肥胖和糖尿病与创伤后应激密切相关。 根据最近的研究，科学家现在实际上认为这种疾病可以预测糖尿病。 肥胖本身并不有害健康，但脂肪组织的功能障碍导致了肥胖 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。 脂质储存能力有限，当它发炎时，通常会达到该极限，导致 许多重要过程的破坏决定了脂肪组织是“健康”还是“不健康”？ 越来越明显的是，脂肪细胞大小的增加也与糖尿病有关。 与脂肪组织的增生潜力成反比，即新的脂肪细胞何时可以形成。 通过细胞增生，脂肪细胞大小保持正常；当增生达到极限时，脂肪细胞大小保持正常； 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。 脂肪细胞源自间充质干细胞（MSC），多能细胞也可以变成肌肉， 骨软骨和其他组织类型如何“决定”遵循哪种分化途径？ 虽然调节脂肪细胞分化（或脂肪生成）的一些途径是已知的，但调节脂肪细胞分化（或脂肪生成）的因素 我们对调节这些途径并从而决定细胞命运知之甚少。 新型脂肪生成信号，即 1-磷酸鞘氨醇 (S1P)，该分子通过 g 蛋白发出信号。 偶联受体以引发多种细胞结果。还有一些与受体无关的功能。 因为我们之前的工作使我们认识到这个分子，因此也认为它是 1-磷酸鞘氨醇。 合成它的酶，鞘氨醇激酶 1 (SK1)，可能在脂肪细胞中发挥作用，我们制作了一个成熟的 我们发现这些动物具有与脂肪细胞特异性 SK1 缺失小鼠非常相似的基础表型。 代谢综合征，但他们并不肥胖，具体来说，他们有胰岛素抵抗，循环水平很高。 瘦素和胰岛素，并显示出非酒精性脂肪肝的迹象。 这些动物脂肪组织中骨和软骨形成途径和信号传导的上调， 支持它们在脂肪生成方面表现出缺陷，我们勇敢地面对1-磷酸鞘氨醇， 在细胞内或细胞外环境中，参与创建脂肪组织微环境 促进源自 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 SK1 和 S1P 下调抗脂肪生成信号通路，并且这是 这些研究不仅将揭示如何保持脂肪组织的“健康”。 预防代谢疾病，但“硬币的另一面”是我们还将发现新的机制 调节脂肪干细胞中的成骨和软骨形成。 目前，这是再生医学的一个主要焦点，我们请求 VA 为这些研究提供资金，因为两者都是。 糖尿病和组织修复是退伍军人群体非常关心的问题，因此这项工作具有高度相关性 为了退伍军人的健康。