| Summary: | 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 <i>Nr4a1</i>,<i> Fgf21</i>,<i> Slc2a3</i>,<i> Pck1</i>, <i>Gck</i>, <i>Hmgcs2</i>, and<i> Bpgm</i>. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated <i>H9c2</i> cardiomyocytes using qPCR. <i>Nr4a1</i> was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of <i>Nr4a1</i> 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 <i>Nr4a1</i> 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 <i>Nr4a1</i> as a key glucose metabolism target in obesity-induced CVD.
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