Role of Ceramide Regulated Fgf13 in AdiposeT issue Biology

神经酰胺调节的 Fgf13 在脂肪问题生物学中的作用

• 批准号: 10289883
• 负责人: Bhagirath Chaurasia
• 金额: $ 36.44万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10289883
• 关键词: Ablation; Adipocytes; Adipose tissue; Adrenergic beta-Agonists; Affect; Agonist; Anabolism; Atherosclerosis; Beds; Biological Assay; Biology; Brown Fat; Cardiac; Cardiovascular Diseases; Cells; Ceramides; Clinic; Coupled; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease Progression; Dyslipidemias; Energy Metabolism; Enzymes; Event; Fatty Liver; Fatty acid glycerol esters; Fibroblast Growth Factor; Genes; Heart Diseases; Heart failure; Human; Hypertriglyceridemia; Immunoprecipitation; Impairment; In Vitro; Individual; Insulin Resistance; Knock-out; Link; Lipids; Locales; Malignant Neoplasms; Maps; Marketing; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Molecular Target; Morphology; Mus; Myocardial Infarction; Nutrient; Obesity; Organism; Pathology; Pathway interactions; Production; Protein Isoforms; Proteins; Regulation; Resistance; Role; Science; Series; Serum; Signal Transduction; Sphingolipids; Stimulus; Stroke; Testing; Thermogenesis; Tissues; Transcript; Work; cardiovascular risk factor; dihydroceramide desaturase; feeding; fibroblast growth factor 13; glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin sensitivity; knock-down; loss of function; mRNA Expression; metabolic rate; novel; novel therapeutic intervention; novel therapeutics; obesity development; prevent; prognostic; programs; protein function; serine palmitoyltransferase; subcutaneous; thermozymocidin; transcriptomics

PROJECT SUMMARY/ABSTRACT Dyslipidemia and insulin resistance predispose individuals to development of diabetes, cancer, myocardial infarction, and stroke. A large body of evidence suggests that a class of toxic lipids, termed ceramides, contribute to these metabolic impairments and the ensuing development of these metabolic disorders. Understanding the role of these lipids in the events that drive metabolic diseases holds great promise for developing new therapies to treat these debilitating conditions. We conducted a series of studies ablating the enzymes required for their production in different body locales to discern which tissues were most sensitive to ceramides. These studies revealed that the lipid has strong and unanticipated effects in adipose tissue. In particular, whole-body, adipose and brown adipose tissue-specific inhibition/deletion of serine palmitoyltransferase (Sptlc), the first enzyme in the enzymatic cascade that drives sphingolipid biosynthesis, in mice markedly altered adipose morphology and metabolism, particularly in subcutaneous and brown adipose tissue. We subsequently excised another gene in the pathway (i.d. dihydroceramide desaturase-1 (Degs1)) from adipose tissue, determining that it elicited a similar spectrum of metabolic improvements. These data indicate that ceramides serve as signals of nutrient excess that alter the metabolic activity of mature adipocytes and subsequently the entire organism. Using microarray screens, we sought to identify ceramide-regulated genes in adipose tissue. The candidate obesity gene Fgf13 was one of the only two transcripts that met the following criteria: (a) increased in mouse subcutaneous white adipose (sWAT) and epididymal white adipose (eWAT) after high fat feeding (HFD); (b) decreased in these depots when the mice were treated with the SPT inhibitor myriocin; (c) decreased in these depots following WAT-specific Sptlc2 depletion; and, (d) decreased in primary adipocytes following myriocin treatment in vitro. We then investigated the function of this protein in vitro and in vivo. Preliminary data using knockdown or knockout approaches suggested that Fgf13 had cell-autonomous, adipocyte-specific, diet-regulated effects on mitochondrial function and thermogenesis. Moreover, mice lacking Fgf13 in adipocytes were resistant to obesity. These data support our hypothesis that FGF13 is a ceramide effector that controls the metabolic activity of mature adipocytes. We will test this idea with the following Specific Aims: 1] to determine the role of FGF13 as a modulator of adipose tissue metabolism and thermogenesis in vivo; 2] to determine the molecular mechanisms linking FGF13 to adipocyte metabolism; and 3] to determine the molecular mechanisms by which b-adrenergic agonists regulate ceramide production and FGF13 expression in primary adipocytes. The findings obtained from these studies could reveal a novel ceramide effector that influences metabolic rate.

项目概要/摘要 血脂异常和胰岛素抵抗使个体易患糖尿病、癌症、心肌病 梗塞和中风。大量证据表明，一类称为神经酰胺的有毒脂质， 导致这些代谢损伤以及随后这些代谢紊乱的发展。 了解这些脂质在导致代谢疾病的事件中的作用为我们带来了巨大的希望 开发新疗法来治疗这些使人衰弱的疾病。我们进行了一系列研究 不同身体部位产生酶所需的酶，以辨别哪些组织对这些酶最敏感 神经酰胺。这些研究表明，脂质对脂肪组织具有强烈且意想不到的作用。在 特别是全身、脂肪和棕色脂肪组织特异性丝氨酸抑制/删除 棕榈酰转移酶 (Sptlc) 是驱动鞘脂生物合成的酶级联中的第一种酶， 小鼠的脂肪形态和代谢显着改变，特别是皮下脂肪和棕色脂肪 组织。随后，我们从该通路中切除了另一个基因（即二氢神经酰胺去饱和酶-1 (Degs1)） 脂肪组织，确定它引起了类似的代谢改善。这些数据表明 神经酰胺作为营养过剩的信号，改变成熟脂肪细胞的代谢活动， 随后是整个有机体。使用微阵列屏幕，我们试图鉴定神经酰胺调节基因 脂肪组织。候选肥胖基因 Fgf13 是仅有的两个满足以下条件的转录本之一 标准：(a) 小鼠皮下白色脂肪 (swAT) 和附睾白色脂肪 (eWAT) 增加 高脂肪喂养（HFD）； (b) 当用 SPT 抑制剂多球壳菌素治疗小鼠时，这些储库减少； (c) 在 WAT 特异性 Sptlc2 耗尽后，这些库中的含量减少； (d) 原代脂肪细胞减少 体外多球壳菌素处理后。然后我们研究了该蛋白质在体外和体内的功能。 使用敲低或敲除方法的初步数据表明 Fgf13 具有细胞自主性、 脂肪细胞特异性、饮食调节对线粒体功能和产热的影响。此外，小鼠缺乏 脂肪细胞中的 Fgf13 对肥胖具有抵抗力。这些数据支持我们的假设：FGF13 是一种神经酰胺 控制成熟脂肪细胞代谢活动的效应器。我们将通过以下具体测试这个想法 目的：1] 确定 FGF13 作为脂肪组织代谢和产热调节剂的作用 体内； 2]确定FGF13与脂肪细胞代谢的分子机制；和3]确定 β-肾上腺素能激动剂调节神经酰胺产生和 FGF13 表达的分子机制 在原代脂肪细胞中。从这些研究中获得的结果可能揭示一种新型神经酰胺效应物 影响新陈代谢率。