Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA128545 | ENA |
REPOSITORIES: ENA
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Project description:Alternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity. Skeletal muscle samples were obtained from 10 lean control subjects and 7 obese subjects with either IGT or DM2 undergoing elective cholecystectomy. Data for liver samples presented in the same manuscript are available at GEO GSE15653. In this analysis RNA was isolated for cRNA preparation and hybridized to Affymetrix Human Genome U133 Plus 2.0 microarrays.
2011-08-02 | E-GEOD-22435 | biostudies-arrayexpress
Project description:Alternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity.
2011-08-03 | GSE22435 | GEO
Project description:Toll-like receptors/Interleukin-1 receptor (IL-1R) signaling plays an important role in High-fat diet (HFD)-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM (IL-1R-associated kinase M)-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduced HFD-induced body weight gain, increased whole body energy expenditure and improved insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induced the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuated HFD-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a novel therapeutic target for obesity.
2022-06-09 | PXD031934 | Pride
Project description:Cytokine signaling has been connected to regulation of metabolism and energy balance. Numerous cytokine gene expression changes are stimulated by accumulation of bile acids in livers of young Foxa2 liver-conditional null mice. We hypothesized that bile acid-induced inflammation in young Foxa2 mutants, once chronic, affects metabolic homeostasis. We found that loss of Foxa2 in the liver results in a premature aging phenotype, including significant weight gain, reduced food intake, and decreased energy expenditure. We show that Foxa2 antagonizes the mammalian target of rapamycin (mTOR) pathway, resulting in increased hepatic lipogenesis and adiposity. While much prior work has focused on adipose tissue in obesity, we discovered a novel age-onset obesity phenotype in a model where genetic deletion occurs only in the liver, underscoring the importance of the role hepatic lipogenesis plays in the development of obesity.
2013-08-19 | E-MTAB-1825 | biostudies-arrayexpress
Project description:Nrg4 is a brown fat-enriched adipokine that binds to the liver and preserves metabolic homeostasis during chronic energy excess. Adipose tissue Nrg4 expression is reduced in mouse and human obesity. Nrg4 deficient mice develp more severe insulin resistance and hepatic fat accumulation upon high-fat diet feeding. We used microarrays to elucidate the metabolic pathways that are regulated by Nrg4 in the liver. Wild type and Neuregulin 4 (Nrg4) knockout mice were fed high-fat diet (Research Diets D12492) for eight weeks. Tissues were harvested under ad lib condition for RNA isolation and microarray hybridization using Affymetrix Mouse MG-430 PM Strip arrays. Three independent pools of WT and KO mouse liver RNA were included in the study. Manuscript title: A brown fat-enriched secreted factor preserves metabolic homeostasis through attenuating hepatic lipogenesis, (journal information TBD)
2014-11-17 | E-GEOD-53877 | biostudies-arrayexpress
Project description:Metabolism in mammals is regulated by the complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in liver. Here we identify glycoprotein nonmetastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor in lipogenesis. Hepatic SREBP pathway inhibition leads to increased transcription of the Gpnmb and promotes the processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver specific knockdown improves metabolic parameters including weight gain reduction and increased insulin sensitivity, likely by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy for obesity and diabetes. Hepatic SREBP pathway inhibition, such as liver-specific ablation of Scap (L-Scap-/-), decreases fatty acid synthesis in liver. Meanwhile, the fatty acid synthesis in white adipose tissue of L-Scap-/- is compensatorily increased. The microarray analysis using the liver RNAs of L-Scap-/- and wild type (WT) mice is performed to identify the up-regulated genes encoding secreted factors in L-Scap-/-.
2019-04-04 | GSE129283 | GEO
Project description:Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-19 (FGF19, mouse FGF15) is a late fed-state gut hormone that decreases hepatic lipid levels by unclear mechanisms. We examined whether FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to DNA methylation and gene repression. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. These results demonstrate that FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.
2020-09-23 | GSE158359 | GEO
Project description:The aim of this study was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro-differentiated adipocytes. MicroRNAs-143-3p and -652-3p are linked to scWAT insulin resistance independently of obesity.
2017-05-01 | GSE87379 | GEO
Project description:Obesity is a growing epidemic affecting billions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(-/-) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases.
2024-04-30 | GSE263865 | GEO
Project description:Analysis of effect of luteolin on lipid metabolism at gene expression level. The hypothesis tested in the present study was that luteolin treatment with obesogenic diet suppressed the hepatic lipogenesis pathways. Conversely, in adipose tissue, luteolin stimulated the lipogenesis pathway and it also simultaneously increased the expression of genes controlling lipolysis and TCA cycle. Results provide important information about the effect on diet-induced obesity and its metabolic complications. Total RNA of liver and adipose tissues was obtained from normal diet, high-fat diet and luteolin added high-fat diet-fed mice and mRNA expression-associated with lipid metabolism was measured.
2014-09-01 | E-GEOD-54189 | biostudies-arrayexpress