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

基本信息

批准号：
10539263
负责人：
Lauren Ashley Cowart
金额：
--
依托单位：
VA VETERANS ADMINISTRATION HOSPITAL
依托单位国家：
美国
项目类别：
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/10539263
关键词：
Abdomen Address Adipocytes Adipose tissue Adrenal Cortex Hormones Adrenergic Receptor Adult Attention Attenuated Award Binding Biogenesis Biology Body fat Brown Fat Cardiovascular Diseases Circulation Data Dexamethasone Diabetes Mellitus Disease Disease Resistance Endocrine Energy Metabolism Energy consumption Exercise Fatty Acids Fatty acid glycerol esters Functional disorder Genes Genetic Transcription Glucocorticoids Glucose Goals Health Health system Heart Histone Deacetylase Inhibitor 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 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

项目摘要

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、糖尿病及其病理结果，包括心血管疾病、肝脏疾病和其他，是退伍军人群体和退伍军人事务部卫生系统的主要负担。研究的目的是确定将肥胖与下游病理生理学联系起来的有害代谢途径。在这个项目的持续时间（从 2009 年第一个优异奖开始）我们已经确定肥胖和糖尿病改变鞘脂代谢，将肥胖与心脏和肝脏的有害结果联系起来。脂质代谢和代谢疾病的关键在于脂肪组织，而脂肪组织一度被认为是脂肪组织。惰性能量储存库，现在被认为具有导致肥胖的内分泌特性减弱会对健康产生负面影响，而且人们还认识到，炎症和脂肪组织的过度扩张脂肪细胞肥大是许多与肥胖相关的病理生理学的基础。除了“白色”脂肪组织之外，脂肪生物学的复杂性也在不断显现。事实上，脂肪组织确实起到储存和释放能量的作用，脂肪组织也可以是“棕色”的——这些“棕色” 仓库对于婴儿和啮齿类动物的体温调节至关重要，但直到最近，人们还认为仓库中不存在仓库。成年人的棕色脂肪组织对有机体有益，因为它利用脂肪酸产生热量，并且它代谢如此活跃，其能量消耗可以降低循环葡萄糖和三酰甘油，从而改善代谢健康。此外，棕色脂肪还分泌有益的激素。尽管成年人体内的棕色脂肪组织储量很小，但最近它已经发挥了积极作用。很明显，白色脂肪组织，即腹部和皮下脂肪，可以被诱导产生受冷、运动、肾上腺素受体刺激等刺激均可引起白色。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，广泛用于治疗各种疾病。在退伍军人群体中，抑制生热脂肪，这可能是众所周知的肥胖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尚未完全了解；然而，我们最近发现鞘氨醇激酶 1，一种产生一类溶血磷脂，对于寒冷引起的褐变很重要。该提案旨在了解这一点。过程并确定该途径是否可以通过一系列的措施来改善代谢稳态研究分为 3 个目标，目标 1 将确定连接鞘氨醇激酶 1 的分子相互作用。目标 2 将测试鞘氨醇激酶 1 的调节是否可以改善白色脂肪组织的褐变。抑制真正的棕色脂肪组织的产热功能以及这是否介导对目标 3 将检查调节鞘脂代谢对整体的体内影响。实现这些目标将为鞘脂和代谢疾病开辟新天地。研究，但也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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.

脂毒性超长链神经酰胺会导致心肌细胞线粒体功能障碍、氧化应激和细胞死亡。

DOI：
发表时间：
2018-03
期刊：
影响因子：
0
作者：
Law, Brittany A;Liao, Xianghai;Moore, Kelsey S;Southard, Abigail;Roddy, Patrick;Ji, Ruiping;Szulc, Zdzislaw;Bielawska, Ala;Schulze, P Christian;Cowart, L Ashley
通讯作者：
Cowart, L Ashley

SHVM-2018 Charleston.

SHVM-2018 查尔斯顿。

DOI：
发表时间：
2020-07-01
期刊：
影响因子：
0
作者：
Cowart, L Ashley;Young, Martin E
通讯作者：
Young, Martin E

Sphingolipids in adipose tissue: What's tipping the scale?

脂肪组织中的鞘脂：是什么改变了规模？

DOI：
10.1016/j.jbior.2018.10.002
发表时间：
2018-12-01
期刊：
Advances in biological regulation
影响因子：
0
作者：
Johana M. Lambert;Johana M. Lambert;Andrea K. Anderson;Andrea K. Anderson;L. A. Cowart
通讯作者：
L. A. Cowart

Sphingolipid regulators of cellular dysfunction in Type 2 diabetes mellitus: a systems overview.

2 型糖尿病细胞功能障碍的鞘脂调节剂：系统概述。