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.

项目总结/文摘