scholarly journals Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 720
Author(s):  
Lihui Men ◽  
Wenting Hui ◽  
Xin Guan ◽  
Tongtong Song ◽  
Xuan Wang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Transcriptome Analysis ◽  
High Fat Diet ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
High Fat ◽  
Altered Expression ◽  
Increased Risk ◽  
H9c2 Cardiomyocytes

Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the critical role of closely interlocked glucose metabolism was determined in HFD-induced cardiac remodeling DEGs, including Nr4a1, Fgf21, Slc2a3, Pck1, Gck, Hmgcs2, and Bpgm. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated H9c2 cardiomyocytes using qPCR. Nr4a1 was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of Nr4a1 by siRNA reversed the PA-induced altered expression of glucose metabolism-related DEGs and hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis, thus indicating that Nr4a1 could modulate glucose metabolism homeostasis by regulating the expression of key enzymes in glycolysis, which may subsequently influence cardiac function in obesity. Overall, we provide a comprehensive understanding of the myocardium transcript molecular framework influenced by HFD and propose Nr4a1 as a key glucose metabolism target in obesity-induced CVD.

scholarly journals Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Jia Zheng ◽  
Ling Zhang ◽  
Jiayi Liu ◽  
Yanli Li ◽  
Junqing Zhang
Keyword(s):  
Glucose Metabolism ◽  
Critical Role ◽  
Protein Restriction ◽  
Male Offspring ◽  
Melanocortin Receptor ◽  
High Fat ◽  
Altered Expression ◽  
Low Protein ◽  
Maternal Protein Restriction ◽  
Fat Feeding

Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = −0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.

scholarly journals Genome-wide identification and characterization of perirenal adipose tissue microRNAs in rabbits fed a high-fat diet

2021 ◽  
Author(s):  
Jie Wang ◽  
Jiahao Shao ◽  
Yanhong Li ◽  
Mauricio A Elzo ◽  
Xianbo Jia ◽  
...  
Keyword(s):  
Intermediate Filament ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Normal Diet ◽  
Pathway Enrichment Analysis ◽  
High Fat ◽  
Cytoskeleton Organization ◽  
Kegg Pathways

MicroRNAs (miRNAs) are a class of endogenous single-stranded RNA molecules that play an important role in gene regulation in animals by pairing with target gene mRNA. Extensive evidence shows that miRNAs are key players in metabolic regulation and the development of obesity. However, the systemic understanding of miRNAs in the adipogenesis of obese rabbit need further investigate. Here, seven small RNA libraries from rabbits fed either a standard normal diet (SND; n = 3) or high-fat diet (HFD; n = 4) were constructed and sequenced. Differentially expressed (DE) miRNAs were identified using the edgeR data analysis package from R. Software miRanda and RNAhybrid were used to predict the target genes of miRNAs. To further explore the functions of DE miRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. A total of 81,449,996 clean reads were obtained from the seven libraries, of which, 52 known DE miRNAs (24 up-regulated, 28 down-regulated) and 31 novel DE miRNAs (14 up-regulated, 17 down-regulated) were identified. GO enrichment analysis revealed that the DE miRNAs target genes were involved in intermediate filament cytoskeleton organization, intermediate filament-based process, and alpha-tubulin binding. DE miRNAs were involved in p53 signaling, linoleic acid metabolism, and other adipogenesis-related KEGG pathways. Our study further elucidates the possible functions of DE miRNAs in rabbit adipogenesis, contributing to the understanding of rabbit obesity.

Abstract 15783: Reduction in Hepatic Tristetraprolin Increases Oxidative Metabolism and Protects Against High-Fat Diet Induced Diabetes

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jason S Shapiro ◽  
Konrad T Sawicki ◽  
Sumeyye Yar ◽  
Chunlei Chen ◽  
Hossein Ardehali
Keyword(s):  
Glucose Metabolism ◽  
Oxidative Metabolism ◽  
High Fat Diet ◽  
Glucose Oxidation ◽  
Fold Increase ◽  
Type Ii Diabetes Mellitus ◽  
High Fat ◽  
Hepatic Expression ◽  
Novel Treatments ◽  
Increased Risk

Introduction: Type II diabetes mellitus (T2DM) is a growing health problem affecting over 29 million Americans and individuals with T2DM have increased mortality after myocardial infarction and stroke. Thus, it is imperative to find novel treatments for diabetes to offset the increased risk of cardiovascular disease (CVD) related mortality. Tristetraprolin (TTP) is an mRNA binding protein first identified as an insulin responsive gene. It binds to AU-rich elements (AREs) in the 3’ untranslated region (UTR) of certain transcripts and promotes their degradation. Reduced TTP expression has been observed in human patients with obesity and insulin resistance, and computational analysis suggests that TTP may bind to and degrade the mRNA of key enzymes involved in glucose oxidation. Thus, we hypothesized that downregulation of TTP would increase glucose oxidation and protect against T2DM. Results: We found hepatic expression of TTP to be decreased in diabetic mice. Using an in silico analysis to identify mRNAs that are targeted by TTP and play a role in glucose metabolism, we identified the pyruvate dehydrogenase-E2 subunit (PDH-E2) to contain several conserved TTP binding sites in its 3’ UTR. PDH-E2 expression was significantly increased (mRNA > 1.4-fold; protein > 2-fold) in hepatocytes isolated from liver-specific TTP knockout (KO) mice. Furthermore, measurement of PDH-E2 mRNA stability showed that PDH-E2 mRNA is significantly stabilized with TTP deletion, indicating that TTP regulates PDH-E2 mRNA. We then assessed whether the regulation of PDH-E2 by TTP alters glucose metabolism. Using Seahorse, we found a 1.7-fold increase in oxidative metabolism in TTP KO cells fed with glucose and pyruvate. This increase was reversed with siRNA mediated downregulation of PDH-E2. Systemically, liver-specific TTP KO mice fed a high-fat diet had significantly lower blood glucose levels after glucose tolerance tests and insulin tolerance tests. Conclusion: Our results suggest that a decrease in TTP protects against the development of T2DM by increasing PDH-E2 expression and subsequent glucose oxidation in the liver. Together, these data provide a novel, potential therapeutic target for T2DM, a significant modifiable risk factor contributing to CVD mortality.

scholarly journals Unveil the transcriptome alteration of POMC neuron in diet-induced obesity

2019 ◽  
Author(s):  
Peng Lyu ◽  
Zhishun Huang ◽  
Qingjun Feng ◽  
Yongfu Su ◽  
Mengying Zheng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
High Fat Diet ◽  
Arcuate Nucleus ◽  
Enrichment Analysis ◽  
Sphingolipid Metabolism ◽  
Pathway Enrichment Analysis ◽  
High Fat ◽  
Transcriptomic Profiling ◽  
Diet Induced Obesity ◽  
Underlying Mechanisms

Abstract Background: Loss of neuron homeostasis in the Arcuate nucleus (ARC) is suggested to be responsible for the development diet-induced-obesity (DIO). We previously reported that loss of Rb1 gene compromised the homeostasis of anorexigenic POMC neurons in ARC and induced obesity in mice.Method: To shed light on how DIO develops, we propose to analyze the transcriptomic alteration of POMC neurons in mice following high fat die (HFD) feeding. We isolated the POMC neurons from established DIO mice and performed transcriptomic profiling on them by RNA-seq.Results: A total of 1,066 genes (628 up-regulated and 438 down-regulated) were identified as differentially expressed genes (DEGs). Pathway enrichment analysis with these DEGs further revealed that ‘cell cycle’, ‘apoptosis’, ‘chemokine signalling’ and ‘sphingolipid metabolism’ pathways were correlated with the development of DIO. Moreover, we validated that the pRb protein, key regulator of ‘cell cycle pathway’, was inactivated by phosphorylation in POMC neurons with HFD feeding. Importantly, reversal of deregulated cell cycle by stereotaxic delivering of the unphosphorylated pRb∆P in ARC significantly meliorated the DIO. Together, our study provides insights into the mechanisms related to the loss of homeostasis of POMC neurons in DIO, and suggests pRb phosphorylation as a potential intervention target to treat DIO. Conclusion: The Arcuate nucleus is the material basis that controlled energy balance and glucose metabolism, which is vulnerable to high-fat-diet (HFD) in diet-induced-obesity (DIO). In this study, we conducted transcriptomic profiling in anorexigenic POMC neurons of ARC with HFD to disclose the underlying mechanisms related with the homeostasis maintenance and the development of DIO. Importantly, we suggest that DIO could be prevented of treated by reversal of the deregulated cell cycle in POMC neurons through targeting pRb phosphorylation. Keywords: High-Fat-Diet (HFD); Diet-Induced Obesity (DIO); POMC neuron; Neuron homeostasis; pRb phosphorylation

scholarly journals N-glycoproteomic analysis of Ginsenoside Rb1 on a hyperlipidemia rat model

2021 ◽  
Author(s):  
Yixin Ma ◽  
Shunyu Ning ◽  
Nan Song ◽  
Si Chen ◽  
Xue Leng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Protein Modification ◽  
Ion Homeostasis ◽  
Enrichment Analysis ◽  
Control Group ◽  
Pathway Enrichment Analysis ◽  
Hypolipidemic Effect ◽  
Ginsenoside Rb1 ◽  
High Fat ◽  
Glycosylation Sites

Abstract Background: Ginsenoside Rb1, known as Renshen in traditional Chinese medicine, is one of the major bioactive saponins isolated from Panax ginseng C.A.Mey. N-glycosylation is the most common type of post-translational modification in cells. The widespread localization of N-glycosylated proteins (N-glycoproteins) between extracellular spaces and on the cell surfaces give them unique advantages as disease biomarkers and drug targets. Previous study found that Ginsenoside Rb1 could potentially play a preventive role in hyperlipidemia. This study aims to reveal the hypolipidemic effect at the protein modification level. Methods: 24 male SD rats were randomly devided into 3 groups: control group (CON), high fat diet group (HFD) and Ginsenoside Rb1 group (Rb1). Both HFD and Rb1 groups were fed with high-fat diet for 12 weeks. The Rb1 group started intragastric administering Ginsenoside Rb1 200 mg·kg -1 ·d -1 at 5th week for 8 weeks, while the CON and HFD group the same amount of normal saline for the same amount of time. Lipid levels and liver histology were assayed to evaluate the effects of Ginsenoside Rb1 intake on hyperlipidemia rats. Furthermore, the workflow by combination of isotope TMT labeling, HILIC enrichment, and high-resolution LC-MS/MS analysis were employed to exploring the mechanisms of regulation role in hyperlipidemia rats.Results: The histopathologic characteristics and biochemical data shows that Ginsenoside Rb1 exhibited regulative effects on hyperlipidemia rats. After being analyzed by N-glycoproteomic, 98 differential N-glycosylation sites on 53 glycoproteins between 2 comparison groups (HFD: CON, Rb1: HFD) were identified. Analyses of N-glycosylation sites distribution found that albumin (Alb) and Serpinc1 were most heavily modified with 6 N-glycosylation sites changed in this work. GO enrichment analysis showed that differential modified glycoproteins were involved in inflammatory response, cellular iron ion homeostasis and positive regulation of cholesterol efflux etc. biosynthetic process. Complement and coagulation cascades was the most significant enriched in the KEGG pathway enrichment analysis. Conclusions: This study presents a comprehensive analysis of a new set of N-glycoproteins which are altered by Ginsenoside Rb1 and offers some valuable clues for novel mechanistic insights into the ragulative mechanism of Ginsenoside Rb1. Results from N-glycoproteomic suggest that to suppress hyperlipidemia, Rb1 may regulates N-glycosylation of Alb, Serpinc1, PON1, Lrp1, Cp and THBS1, as well as differentially modified glycoproteins in complement and coagulation cascades, which in turn improve the imbalance of lipid homeostasis.

scholarly journals Genome-Wide DNA Methylation Changes of Perirenal Adipose Tissue in Rabbits Fed a High-Fat Diet

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2213
Author(s):  
Jiahao Shao ◽  
Xue Bai ◽  
Ting Pan ◽  
Yanhong Li ◽  
Xianbo Jia ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Enrichment Analysis ◽  
Epigenetic Mechanism ◽  
Pathway Enrichment Analysis ◽  
High Fat ◽  
Perirenal Adipose Tissue ◽  
Pathway Enrichment ◽  
Genome Wide

DNA methylation is an epigenetic mechanism that plays an important role in gene regulation without an altered DNA sequence. Previous studies have demonstrated that diet affects obesity by partially mediating DNA methylation. Our study investigated the genome-wide DNA methylation of perirenal adipose tissue in rabbits to identify the epigenetic changes of high-fat diet-mediated obesity. Two libraries were constructed pooling DNA of rabbits fed a standard normal diet (SND) and DNA of rabbits fed a high-fat diet (HFD). Differentially methylated regions (DMRs) were identified using the option of the sliding window method, and online software DAVID Bioinformatics Resources 6.7 was used to perform Gene Ontology (GO) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of DMRs-associated genes. A total of 12,230 DMRs were obtained, of which 2305 (1207 up-regulated, 1098 down-regulated) and 601 (368 up-regulated, 233 down-regulated) of identified DMRs were observed in the gene body and promoter regions, respectively. GO analysis revealed that the DMRs-associated genes were involved in developmental process (GO:0032502), cell differentiation (GO:0030154), and lipid binding (GO:0008289), and KEGG pathway enrichment analysis revealed the DMRs-associated genes were enriched in linoleic acid metabolism (KO00591), DNA replication (KO03030), and MAPK signaling pathway (KO04010). Our study further elucidates the possible functions of DMRs-associated genes in rabbit adipogenesis, contributing to the understanding of HFD-mediated obesity.

scholarly journals Genome-wide Identification and Characterization of Perirenal Adipose Tissue MiRNAs in Rabbits Fed With a High-fat Diet

2020 ◽  
Author(s):  
Jie Wang ◽  
Jiahao Shao ◽  
Yanhong Li ◽  
Mauricio A. Elzo ◽  
Xianbo Jia ◽  
...  
Keyword(s):  
Intermediate Filament ◽  
High Fat Diet ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Normal Diet ◽  
Pathway Enrichment Analysis ◽  
High Fat ◽  
Alpha Tubulin ◽  
Cytoskeleton Organization ◽  
Kegg Pathways

Abstract Background MicroRNAs (miRNAs) are a class of endogenous single-stranded RNA molecules that play an important role in gene regulation in animals by pairing with target gene mRNAs. However, the functions of miRNAs in the adipogenesis of obese rabbits are poorly understood. Methods Six small RNA libraries from rabbits under a standard normal diet (SND; n = 3) and a high-fat diet (HFD; n = 3) were constructed and sequenced. Differentially expressed (DE) miRNAs were identified using the edgeR data analysis package from R. Software miRanda and RNAhybrid were used to predict the target genes of miRNAs. To further explore the functions of DE miRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Results A total of 69577441 clean reads were obtained from the six libraries, of which, 52 known DE miRNAs (24 up-regulated, 28 down-regulated) and 31 novel DE miRNAs (14 up-regulated, 17 down-regulated) were identified. GO enrichment analysis revealed that the DE miRNAs target genes were involved in intermediate filament cytoskeleton organization, intermediate filament-based process, and alpha-tubulin binding. DE miRNAs were involved in p53 signaling, linoleic acid metabolism, and other adipogenesis-related KEGG pathways. Conclusions Our study further elucidates the possible functions of DE miRNAs in rabbit adipogenesis, contributing to the understanding of rabbit obesity.

Non-Fasting Factor VII Coagulant Activity (FVII:C) Increased by High-Fat Diet

1994 ◽  
Vol 71 (06) ◽  
pp. 755-758 ◽  
Author(s):  
E M Bladbjerg ◽  
P Marckmann ◽  
B Sandström ◽  
J Jespersen
Keyword(s):  
High Fat Diet ◽  
Fat Content ◽  
Factor Vii ◽  
Amidolytic Activity ◽  
High Fat ◽  
Low Fat Diet ◽  
Increased Risk ◽  
Coagulant Activity ◽  
High Fat Diets ◽  
Fat Diets

SummaryPreliminary observations have suggested that non-fasting factor VII coagulant activity (FVII:C) may be related to the dietary fat content. To confirm this, we performed a randomised cross-over study. Seventeen young volunteers were served 2 controlled isoenergetic diets differing in fat content (20% or 50% of energy). The 2 diets were served on 2 consecutive days. Blood samples were collected at 8.00 h, 16.30 h and 19.30 h, and analysed for triglycerides, FVII coagulant activity using human (FVII:C) or bovine thromboplastin (FVII:Bt), and FVII amidolytic activity (FVIPAm). The ratio FVII:Bt/FVII:Am (a measure of FVII activation) increased from fasting levels on both diets, but most markedly on the high-fat diet. In contrast, FVII: Am (a measure of FVII protein) tended to decrease from fasting levels on both diets. FVII:C rose from fasting levels on the high-fat diet, but not on the low-fat diet. The findings suggest that high-fat diets increase non-fasting FVII:C, and consequently may be associated with increased risk of thrombosis.

scholarly journals Aberrant expression of HDL-bound microRNA induced by a high-fat diet in a pig model: implications in the pathogenesis of dyslipidaemia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guoyuan Sui ◽  
Lianqun Jia ◽  
Nan Song ◽  
Dongyu Min ◽  
Si Chen ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
High Fat Diet ◽  
Enrichment Analysis ◽  
Diet Group ◽  
High Fat ◽  
Positive Regulation ◽  
Aberrant Expression ◽  
Balanced Diet ◽  
Mirna Sequencing

Abstract Background A high-fat diet can affect lipid metabolism and trigger cardiovascular diseases. A growing body of studies has revealed the HDL-bound miRNA profiles in familial hypercholesterolaemia; in sharp contrast, relevant studies on high-fat diet-induced dyslipidaemia are lacking. In the current study, HDL-bound miRNAs altered by a high-fat diet were explored to offer some clues for elucidating their effects on the pathogenesis of dyslipidaemia. Methods Six pigs were randomly divided into two groups of three pigs each, namely, the high-fat diet and the balanced diet groups, which were fed a high-fat diet and balanced diet separately for six months. HDL was separated from plasma, which was followed by dissociation of the miRNA bound to HDL. miRNA sequencing of the isolated miRNA was performed to identify the differential expression profiles between the two groups, which was validated by real-time PCR. TargetScan, miRDB, and miRWalk were used for the prediction of genes targeted by the differential miRNAs. Results Compared with the balanced diet group, the high-fat diet group had significantly higher levels of TG, TC, LDL-C and HDL-C at six months. miRNA sequencing revealed 6 upregulated and 14 downregulated HDL-bound miRNAs in the high-fat diet group compared to the balanced diet group, which was validated by real-time PCR. GO enrichment analysis showed that dysregulated miRNAs in the high-fat diet group were associated with the positive regulation of lipid metabolic processes, positive regulation of lipid biosynthetic processes, and positive regulation of Ras protein signal transduction. Insulin resistance and the Ras signalling pathway were enriched in the KEGG pathway enrichment analysis. Conclusions Twenty HDL-bound miRNAs are significantly dysregulated in high-fat diet-induced dyslipidaemia. This study presents an analysis of a new set of HDL-bound miRNAs that are altered by a high-fat diet and offers some valuable clues for novel mechanistic insights into high-fat diet-induced dyslipidaemia. Further functional verification study using a larger sample size will be required.

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