Sphingolipids in the Pathophysiology of Obesity and Diabetes

肥胖、糖尿病及其病理结果，包括心血管疾病、肝脏疾病和 其他的，是退伍军人和退伍军人卫生系统的主要负担。我们的首要目标是 研究旨在确定将肥胖与下游病理生理联系起来的有害新陈代谢途径。完毕 在这个项目的持续时间(从2009年的第一个功勋奖开始)，我们已经确定肥胖和 糖尿病会改变鞘脂代谢，将肥胖与心脏和肝脏的有害后果联系起来。在症结所在 脂代谢和代谢性疾病的关键在于脂肪组织。脂肪组织，虽然曾经被认为是一种 惰性能量储存库，现在被认为具有导致肥胖的内分泌特性 对于负面的健康后果，人们也认识到，炎症和脂肪组织的过度膨胀 脂肪细胞肥大是许多肥胖相关病理生理学的基础。 脂肪生物学的复杂性正在不断显现。除了白色的脂肪组织 事实上，脂肪组织是用来储存和释放能量的，脂肪组织也可以是“棕色的”--这些“棕色的” 仓库对婴儿和啮齿类动物的体温调节至关重要，直到最近，人们还认为 成年人类。棕色脂肪组织对机体有益，因为它使用脂肪酸来产生热量，而且它 它的代谢非常活跃，它的能量消耗可以降低循环中的葡萄糖和三酰甘油， 从而改善新陈代谢健康。此外，棕色脂肪还会分泌有益的荷尔蒙 为它的积极影响做出贡献。虽然成年人的棕色脂肪组织储藏量很小，但最近已经很少了 很明显，白色脂肪组织，即腹部和皮下脂肪，可以被诱导为 像棕色一样的状态。冷暴露、运动和肾上腺素能受体刺激等刺激可导致白色 脂肪细胞会产生类似棕色的特性。这种所谓的米色脂肪组织的可塑性很吸引人。 作为一种改善新陈代谢健康的潜在方法。糖皮质激素，广泛用于各种疾病 在退伍军人群体中，抑制热源性脂肪，这可能是众所周知的肥胖症的基础 糖皮质激素治疗的特性。 白色脂肪细胞转化为棕色或米色脂肪细胞的分子机制仍然存在 不完全了解；然而，我们最近发现鞘氨醇激酶1，一种能产生 溶血磷脂是一类对低温诱导褐变起重要作用的物质。这项提案试图理解这一点 处理并确定这一途径是否可以通过一系列的靶向改善代谢动态平衡 研究分为3个目标。目标1将确定连接神经鞘氨醇激酶1的分子相互作用 伴有白色脂肪组织的褐变。AIM 2将测试鞘氨醇激酶1的调制是否可以 抑制真正的棕色脂肪组织的生热功能，以及这是否介导了对 地塞米松。目的3将检查在体内调节鞘磷脂代谢的影响 新陈代谢功能。实现这些目标将在鞘脂和代谢性疾病方面开辟新的天地 研究，但也将扩展我们的知识，即操纵棕色或米色脂肪组织如何影响 人类健康。

Obesity, diabetes, and their pathological outcomes including cardiovascular disease, liver disease, and others, are a major burden on the Veteran population and the VA health system. The overarching goal of our research is to identify deleterious metabolic pathways linking obesity to downstream pathophysiology. Over the duration of this project (started with the first Merit award in 2009) we have determined that obesity and diabetes change sphingolipid metabolism linking obesity to deleterious outcomes in heart and liver. At the crux of lipid metabolism and metabolic disease lies adipose tissue. Adipose tissue, while once thought to be an inert energy storage depot, is now recognized to have endocrine properties that are blunted in obesity leading to negative health outcomes, and it is also recognized that inflammation and over-expansion of adipose tissue through adipocyte hypertrophy underlies much obesity-related pathophysiology. The complexity of adipose biology is continuing to emerge. In addition to the ‘white’ adipose tissue depots that do in fact serve to store and release energy, adipose tissue can also be ‘brown’—these ‘brown’ depots are critical for thermoregulation in infants and rodents, and, until recently, were not thought to exist in adult humans. Brown adipose tissue is beneficial for the organism as it uses fatty acids to generate heat, and it is so metabolically active that its energy consumption can lower circulating glucose and triacylglycerols, thereby improving metabolic health. Moreover, brown adipose also secretes beneficial hormones that contribute to its positive effects. While brown adipose tissue depots in adult humans are small, it has recently become apparent that white adipose tissue, i.e. abdominal and subcutaneous adipose, can be induced to a brown-like state. Stimuli such as cold exposure, exercise, and adrenergic receptor stimulation can cause white adipocytes to accrue brown-like properties. The plasticity of this so-called ‘beige’ adipose tissue is attractive as a potential method by which to improve metabolic health. Glucocorticoids, widely used for various ailments in the Veteran population, suppress thermogenic adipose, which may underlie the well known obesogenic properties of glucocorticoid treatment. Molecular mechanisms by which white adipocytes convert to brown-like or ‘beige’ adipocytes remain incompletely understood; however, we recently found that Sphingosine Kinase 1, a lipid kinase that generates a class of lysophospholipids, is important for cold-induced browning. This proposal seeks to understand this process and determine whether this pathway can be targeted to improve metabolic homeostasis by a series of studies organized into 3 aims. Aim 1 will determine the molecular interactions that link Sphingosine Kinase 1 with browning of white adipose tissue. Aim 2 will test whether modulation of Sphingosine Kinase 1 can suppress thermogenic function of bona-fide brown adipose tissue and whether this mediates the response to dexamethasone. Aim 3 will examine the in vivo effects of modulating sphingolipid metabolism on overall metabolic function. Accomplishing these aims will break new ground in sphingolipid and metabolic disease research but will also extend our knowledge of how manipulating brown or beige adipose tissue can impact human health.