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Transcriptomic and microRNA analyses of gene networks regulated by eicosapentaenoic acid in brown adipose tissue of diet-induced obese mice.

ABSTRACT: Brown adipose tissue (BAT) dissipates chemical energy as heat via thermogenesis and protects against obesity by increasing energy expenditure. However, regulation of BAT by dietary factors remains largely unexplored at the mechanistic level. We investigated the effect of eicosapentaenoic acid (EPA) on BAT metabolism. Male C57BL/6J (B6) mice were fed either a high-fat diet (HF, 45% kcal fat) or HF diet supplemented with EPA (HF-EPA, 6.75% kcal EPA) for 11?weeks. RNA sequencing (RNA-Seq) and microRNA (miRNA) profiling were performed on RNA from BAT using Illumina HiSeq and Illumina Genome Analyzer NextSeq, respectively. We conducted pathway analyses using ingenuity pathway analysis software (IPA®) and validated some genes and miRNAs using qPCR. We identified 479 genes that were differentially expressed (2-fold change, n?=?3, P???0.05) in BAT from HF compared to HF-EPA. Genes negatively correlated with thermogenesis such as hypoxia inducible factor 1 alpha subunit inhibitor (Hif1an), were downregulated by EPA. Pathways related to thermogenesis such as peroxisome proliferator-activated receptor (PPAR) were upregulated by EPA while pathways associated with obesity and inflammation such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) were downregulated by EPA. MiRNA profiling identified nine and six miRNAs that were upregulated and downregulated by EPA, respectively (log2 fold change?>?1.25, n?=?3, P???0.05). Key regulatory miRNAs which were involved in thermogenesis, such as miR-455-3p and miR-129-5p were validated using qPCR. In conclusion, the depth of transcriptomic and miRNA profiling revealed novel mRNA-miRNA interaction networks in BAT which are involved in thermogenesis, and regulated by EPA.

SUBMITTER: Pahlavani M

PROVIDER: S-EPMC6298436 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic and microRNA analyses of gene networks regulated by eicosapentaenoic acid in brown adipose tissue of diet-induced obese mice.

Pahlavani Mandana M Wijayatunga Nadeeja N NN Kalupahana Nishan S NS Ramalingam Latha L Gunaratne Preethi H PH Coarfa Cristian C Rajapakshe Kimal K Kottapalli Pratibha P Moustaid-Moussa Naima N

Biochimica et biophysica acta. Molecular and cell biology of lipids 20180925 12

Brown adipose tissue (BAT) dissipates chemical energy as heat via thermogenesis and protects against obesity by increasing energy expenditure. However, regulation of BAT by dietary factors remains largely unexplored at the mechanistic level. We investigated the effect of eicosapentaenoic acid (EPA) on BAT metabolism. Male C57BL/6J (B6) mice were fed either a high-fat diet (HF, 45% kcal fat) or HF diet supplemented with EPA (HF-EPA, 6.75% kcal EPA) for 11 weeks. RNA sequencing (RNA-Seq) and micro ...[more]

PMID: 30261280

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Project description:Interscapular brown adipose tissue (BAT) plays an important role in controlling glucose homeostasis. Increased glucose entry and glycolysis in BAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1), markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in BAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in BAT by injecting adeno-associated viruses (AAVs) expressing HCAR1 into the BAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in BAT resulted in augmented glucose uptake by BAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated BAT temperature associated with increased thermogenic gene expression in BAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in BAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in hormone-sensitive lipase (HSL) phosphorylation and increased lipogenic enzyme gene expression in BAT. Unlike DIO mice, overexpressing HCAR1 in BAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in BAT promotes glucose entry and reduces lipolysis in BAT of male DIO mice. As activation of HCAR1 in BAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, our study suggests that interoceptive lactate detection via HCAR1 in BAT can regulate glucose and lipid substrate utilization and/or availability to promote healthy metabolism.NEW & NOTEWORTHY HCAR1 expressed in BAT can promote glucose entry and reduce lipolysis, resulting in body weight loss and increased insulin sensitivity. Hence, targeting HCAR1 in BAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.

Dataset Information

Transcriptomic and microRNA analyses of gene networks regulated by eicosapentaenoic acid in brown adipose tissue of diet-induced obese mice.

Publications

Transcriptomic and microRNA analyses of gene networks regulated by eicosapentaenoic acid in brown adipose tissue of diet-induced obese mice.

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