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: 10369950
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369950
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adrenal Cortex Hormones; Adrenergic Receptor; Adult; Attention; Attenuated; Award; Binding; Biogenesis; Biology; Blood Circulation; Body fat; Brown Fat; Cardiovascular Diseases; Consumption; Data; Dexamethasone; Diabetes Mellitus; Disease; Disease Resistance; Endocrine; Energy Metabolism; Exercise; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genes; Genetic Transcription; Glucocorticoids; Glucose; Goals; Health; Health system; Heart; Histone Deacetylase; Homeostasis; Hormones; Human; Hypertrophy; Infant; Inflammation; Insulin Resistance; Knockout Mice; Knowledge; Link; Lipids; Liver; Liver diseases; Lysophospholipids; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Nature; Obesity; Organism; Outcome; Oxidative Phosphorylation; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphotransferases; Physiologic Thermoregulation; Population; Post-Traumatic Stress Disorders; Process; Production; Property; Regulation; Research; Research Support; Resistance; Rodent; Role; SPHK1 enzyme; Series; Sphingolipids; Stimulus; Testing; Thermogenesis; Triglycerides; Up-Regulation; Veterans; Weight Gain; Work; adipokines; base; body system; diet-induced obesity; disease phenotype; fatty liver disease; improved; in vivo; interest; lipid metabolism; metabolic phenotype; military veteran; mouse model; non-alcoholic fatty liver disease; obesogenic; p38 Mitogen Activated Protein Kinase; prevent; programs; response; side effect; sphingosine kinase; subcutaneous; transdifferentiation; Abdomen; Address; Adipocytes; Adipose tissue; Adrenal Cortex Hormones; Adrenergic Receptor; Adult; Attention; Attenuated; Award; Binding; Biogenesis; Biology; Blood Circulation; Body fat; Brown Fat; Cardiovascular Diseases; Consumption; Data; Dexamethasone; Diabetes Mellitus; Disease; Disease Resistance; Endocrine; Energy Metabolism; Exercise; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genes; Genetic Transcription; Glucocorticoids; Glucose; Goals; Health; Health system; Heart; Histone Deacetylase; Homeostasis; Hormones; Human; Hypertrophy; Infant; Inflammation; Insulin Resistance; Knockout Mice; Knowledge; Link; Lipids; Liver; Liver diseases; Lysophospholipids; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Nature; Obesity; Organism; Outcome; Oxidative Phosphorylation; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphotransferases; Physiologic Thermoregulation; Population; Post-Traumatic Stress Disorders; Process; Production; Property; Regulation; Research; Research Support; Resistance; Rodent; Role; SPHK1 enzyme; Series; Sphingolipids; Stimulus; Testing; Thermogenesis; Triglycerides; Up-Regulation; Veterans; Weight Gain; Work; adipokines; base; body system; diet-induced obesity; disease phenotype; fatty liver disease; improved; in vivo; interest; lipid metabolism; metabolic phenotype; military veteran; mouse model; non-alcoholic fatty liver disease; obesogenic; p38 Mitogen Activated Protein Kinase; prevent; programs; response; side effect; sphingosine kinase; subcutaneous; transdifferentiation

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.

肥胖，糖尿病及其病理结局，包括心血管疾病，肝病和 其他人是资深人口和VA卫生系统的主要伯恩伯恩（Burnen）。我们的总体目标 研究是为了确定将肥胖与下游病理生理学联系起来的有害代谢途径。超过 该项目的持续时间（从2009年获得第一个优异奖开始），我们确定了肥胖症和 糖尿病会改变将肥胖与心脏和肝脏中有害结果联系起来的鞘脂代谢。在关键 脂质代谢和代谢疾病的脂肪组织。脂肪组织，而曾经被认为是 惰性储能库现在被认为具有内分泌特性，在肥胖症中钝性 对健康结果负面的结果，还认识到脂肪组织的感染和过度膨胀 通过脂肪细胞肥大构成了许多与肥胖相关的病理生理学。 脂肪生物学的复杂性正在继续出现。除了“白色”脂肪组织 实际上确实有助于储存和释放能量的沉积物，脂肪组织也可以是“棕色” - 这些“棕色” 沉积对于婴儿和啮齿动物的温度调节至关重要，直到最近才被认为存在 成年人。棕色脂肪组织对生物体有益，因为它使用脂肪酸来产生热量，并且 如此代谢活跃，以至于其能耗可以降低循环葡萄糖和三酰基甘油， 从而改善了代谢健康。此外，布朗脂肪还分泌有益的恐怖 促进其积极影响。虽然成年人类中的棕色脂肪组织沉积物很小，但最近有 显然可以将白色脂肪组织，即腹部和皮下脂肪，可以诱导到A 棕色状态。刺激，例如冷暴露，运动和肾上腺素受体刺激会导致白色 脂肪细胞具有棕色的特性。这种所谓的“米色”脂肪组织的可塑性很有吸引力 作为改善代谢健康的潜在方法。糖皮质激素，广泛用于各种疾病 在退伍军人人口中，抑制热脂肪，这可能是众所周知的有机基因 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保留 不完全理解；但是，我们最近发现鞘氨醇激酶1，一种生成的脂质激酶 一类溶物磷脂对于冷诱导的褐变很重要。该提议试图理解这一点 过程并确定是否可以针对该途径来改善代谢稳态。 研究组织为3个目标。 AIM 1将确定连接鞘氨酸激酶1的分子相互作用 白色脂肪组织褐变。 AIM 2将测试鞘氨醇激酶1的调节是否可以 抑制真正的棕色脂肪组织的热功能，这是否介导 地塞米松。 AIM 3将检查调节鞘脂代谢对整体的体内影响 代谢功能。实现这些目标将在鞘脂和代谢疾病中打破新的基础 研究，但还将扩展我们对操纵棕色或米色脂肪组织如何影响的知识 人类健康。