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SnoRNA antagonizes IL-15-mediated lipolysis and promotes obesity

ABSTRACT: Obesity has long been considered one of the most important risk factors for a number of cancer types, including breast cancer and remains one the more severe disease concerns. However, the functional importance of noncoding RNA elements remains elusive. Here, we report the upregulation of SNORD46 in obesity serum. The expression status of SNORD46 is correlated with donor’s body mass index (BMI). The expression of SNORD46 in adipocytes was regulated in a CEBP-beta-dependent manner. Mechanically, adipocyte-expressed SNORD46 bound with interleukin-15 (IL-15) in serum, by which Snord46 G11A mutant exhibited enhanced interaction with IL-15. A knockin mouse strain harboring a Snord46 G11A mutation (referred as Snord46mut/mut mice) exhibited obesity and obesity associated complexities compared to wild type or heterozygous littermates. The SNORD46-IL-15 interaction blocked IL-15-dependent non-canonical signaling events, which contained the tyrosine-protein kinase Fer-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL). Consequently, the obesity-expressed SNORD46 suppressed the IL-15 triggered, Fer-dependent phosphorylation of CD36 and MGLL, leading to inhibited lipase of adipocytes. SNORD46 locked nucleic acids (LNAs) effectively conquered the inhibitory effect of SNORD46 and exhibited anti-obesity effects. Hence, our findings demonstrated the functional importance of snoRNAs in obesity and the efficacy of snoRNA LNAs for antagonizing obesity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213465 | GEO | 2022/09/18

REPOSITORIES: GEO

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Project description:This SuperSeries is composed of the following subset Series:; GSE8290: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 1; GSE8291: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 2; GSE8292: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 3; GSE8295: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 4; GSE8302: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 5; PPARalpha is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARalpha in hepatic lipid metabolism, many PPARalpha-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARalpha-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARalpha target genes, livers from several animal studies in which PPARalpha was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARalpha-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARalpha-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein beta polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARalpha agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARalpha. Our study illustrates the power of transcriptional profiling to uncover novel PPARalpha-regulated genes and pathways in liver. Experiment Overall Design: Refer to individual Series

Project description:PPARÎ± is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARÎ± in hepatic lipid metabolism, many PPARÎ±-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARÎ±-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARÎ± target genes, livers from several animal studies in which PPARÎ± was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARÎ±-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARÎ±-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein Î² polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARÎ± agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARÎ±. Our study illustrates the power of transcriptional profiling to uncover novel PPARÎ±-regulated genes and pathways in liver. Experiment Overall Design: Primary rat and mouse hepatocytes were incubated in the presence (10 uM) or absence of the synthetic PPARÎ± ligand Wy14643 for 24 hours. Primary human hepatocytes were incubated in the presence (50 uM) or absence of Wy14643 for 12 hours. Total RNA was pooled within groups and hybridized onto Rat Genome 230 2.0 Arrays, Mouse Genome 430 2.0 Arrays or Human Genome U133 Plus 2.0 Arrays.

Project description:PPARÎ± is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARÎ± in hepatic lipid metabolism, many PPARÎ±-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARÎ±-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARÎ± target genes, livers from several animal studies in which PPARÎ± was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARÎ±-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARÎ±-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein Î² polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARÎ± agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARÎ±. Our study illustrates the power of transcriptional profiling to uncover novel PPARÎ±-regulated genes and pathways in liver. Experiment Overall Design: 3-5 months old male pure bred wild-type (129S1/SvImJ) and PPARÎ±-null (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARÎ±-null mice were treated with the synthetic PPARÎ± ligand Wy14643 (0.1% w/w) mixed in the food, or normal food (control) for 5 days (n=4 per group). Liver total RNA from biological replicates was hybridized onto Affymetrix mouse genome 430 2.0 GeneChip arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

Project description:PPARÎ± is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARÎ± in hepatic lipid metabolism, many PPARÎ±-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARÎ±-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARÎ± target genes, livers from several animal studies in which PPARÎ± was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARÎ±-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARÎ±-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein Î² polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARÎ± agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARÎ±. Our study illustrates the power of transcriptional profiling to uncover novel PPARÎ±-regulated genes and pathways in liver. Experiment Overall Design: 3-5 months old male pure bred wild-type (129S1/SvImJ) and PPARÎ±-null (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARÎ±-null mice fasted for 4 hours received a single dose of WY14643 (400 Î¼l of 10 mg/ml WY14643) or vehicle and were killed 6 hours later (n=3-5 per group). Liver total RNA from biological replicates was hybridized onto Affymetrix mouse genome 430 2.0 GeneChip arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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SnoRNA antagonizes IL-15-mediated lipolysis and promotes obesity

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