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: 10550189
• 负责人: Bhagirath Chaurasia
• 金额: $ 38.63万
• 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/10550189
• 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; Predisposition; 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; gain of function; glucose tolerance; improved; in vivo; inhibitor; 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.

项目摘要/摘要 血脂异常和胰岛素抵抗感易感糖尿病，癌症，心肌的发育 梗塞和中风。大量证据表明，一类有毒脂质，称为神经酰胺， 促进这些代谢障碍以及这些代谢疾病的随之而来的发展。 了解这些脂质在驱动代谢疾病的事件中的作用对 开发新的疗法来治疗这些令人衰弱的疾病。我们进行了一系列研究 其在不同人体中生产所需的酶才能辨别哪些组织对 神经酰胺。这些研究表明，脂质在脂肪组织中具有强大而意外的作用。在 特定的，全身，脂肪和棕色脂肪组织特异性抑制/丝氨酸缺失 棕榈酰转移酶（SPTLC），酶级联的第一种驱动鞘脂生物合成的酶，在 小鼠明显改变了脂肪形态和代谢，特别是在皮下和棕色脂肪中 组织。随后，我们从途径（I.D. Dihydrocamide deatatrose-1（degs1））中切除了另一个基因 脂肪组织，确定它引起了类似的代谢改进。这些数据表明 该神经酰胺是营养过量的信号，改变了成熟脂肪细胞的代谢活性和 随后整个生物体。使用微阵列屏幕，我们试图确定神经酰胺调节的基因 脂肪组织。候选肥胖基因FGF13是仅有的两个成绩单之一 标准：（a）在小鼠皮下白色脂肪（SWAT）和附睾白脂肪（EWAT）中增加 高脂肪进食（HFD）； （b）当小鼠用SPT抑制剂霉菌素处理时，这些仓库中的减少； （c）在特异性SPTLC2耗竭后，这些仓库中的这些仓库减少； （d）原发性脂肪细胞减少 在体外进行肉豆蔻素治疗后。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， 脂肪细胞特异性，饮食调节对线粒体功能和热发生的影响。而且，老鼠缺乏 脂肪细胞中的FGF13对肥胖具有抗性。这些数据支持我们假设FGF13是神经酰胺 控制成熟脂肪细胞代谢活性的效应子。我们将以以下特定的特定来测试这个想法 目的：1]确定FGF13作为脂肪组织代谢和生热的调节剂的作用 体内2]确定将FGF13与脂肪细胞代谢联系起来的分子机制；和3]确定 B-肾上腺素能激动剂调节神经酰胺和FGF13表达的分子机制 在原发性脂肪细胞中。从这些研究中获得的发现可以揭示出一种新型的神经酰胺效应子，即 影响代谢率。