RESUMEN
This study aims to investigate the global profiling of genes and miRNAs expression to explore the regulatory effects of eicosapentaenoic acid (EPA) in visceral adipose tissue (VAT) of obese mice. We used male mice, fed either a high-fat diet (HF) or HF supplemented with EPA (HF-EPA), for 11 weeks. RNA, and small RNA profiling, were performed by RNAseq analysis. We conducted analyses using Ingenuity Pathway Analysis software (IPA®) and validated candidate genes and miRNAs related to lipid mediators and inflammatory pathways using qRT-PCR. We identified 153 genes differentially downregulated, and 62 microRNAs differentially expressed in VAT from HF-EPA compared to HF. Genes with a positive association with inflammation, chemotaxis, insulin resistance, and inflammatory cell death, such as Irf5, Alox5ap, Tlrs, Cd84, Ccr5, Ccl9, and Casp1, were downregulated by EPA. Moreover, EPA significantly reduced LTB4 levels, a lipid mediator with a central role in inflammation and insulin resistance in obesity. The pathways and mRNA/microRNA interactions identified in our study corroborated with data validated for inflammatory genes and miRNAs. Together, our results identified key VAT inflammatory targets and pathways, which are regulated by EPA. These targets merit further investigation to better understand the protective mechanisms of EPA in obesity-associated inflammation.
Asunto(s)
Antiinflamatorios/farmacología , Ácido Eicosapentaenoico/farmacología , Grasa Intraabdominal/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Ácido Eicosapentaenoico/uso terapéutico , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Inflamación/metabolismo , Grasa Intraabdominal/efectos de los fármacos , Leucotrieno B4/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , MicroARNs/metabolismo , Obesidad/inducido químicamente , Obesidad/genética , Obesidad/metabolismo , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Superficie Celular/genética , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , TranscriptomaRESUMEN
Serum levels of leukotriene-B4 (LTB4) are increased in type 1 diabetes (T1D) and it mediates systemic inflammation and macrophage reprogramming associated with this condition. Herein, we investigated the involvement of LTB4 in adiposity loss, hyperlipidemia, and changes in macrophage metabolism in a mouse model of streptozotocin-induced T1D. LTB4 receptor (BLT1) antagonist u75302 was employed to block LTB4 effects. As expected, hypoinsulinemia in T1D was associated with hyperglycemia, low levels of glucagon, hyperlipidemia, significant body fat loss, and increased white adipose tissue expression of Fgf21, a marker for lipolysis. With the exception of hyperglycemia and hypoglucagonemia, blockade of LTB4 signaling reverted these parameters in T1D mice. Along with hyperlipidemia, macrophages from T1D mice exhibited higher lipid uptake and accumulation. These cells also had enhanced glycolysis and oxidative metabolism and these parameters were dependent on the mitochondrial uncoupling respiration, as evidenced by elevated expression of oxidation markers carnitine palmitoyltransferase and uncoupling protein 1. Interestingly, all these parameters were at least partially reverted in T1D mice treated with u75302. Altogether, these findings suggest that in T1D mice LTB4/BLT1 is involved in the fat loss, hyperlipidemia, and increased macrophage lipid uptake and metabolism with an important involvement of mitochondrial uncoupling activity. These previously unrecognized LTB4/BLT1 functions may be explored in future to therapeutically alleviate severity of hyperlipidemia and systemic inflammation in T1D.