RESUMEN
Low birth weight (LBW) and macrosomia have been associated with later-in-life metabolic alterations. The aim of this study was to elucidate whether the expression levels of circulating microRNAs (c-miRNAs) associated with adult metabolic diseases are also dysregulated in newborns with LBW or macrosomia. The expression levels of five microRNAs (miRNAs) associated with metabolic diseases were quantified in dried blood spots of newborns with adequate birth weight, LBW and macrosomia by stem-loop real-time polymerase chain reaction. miR-29a-5p, miR-126-3p, miR-221-3p, and miR-486-5p were significantly overexpressed in newborns with macrosomia and showed no significant change in the LBW group compared to normal weight controls. miR-320a showed no statistical difference among groups. We predicted the putative target genes and pathways of the overexpressed miRNAs with bioinformatic tools. Bioinformatic analyses of overexpressed miRNAs predicted target genes involved in carbohydrate metabolism, participate in FoxO and PI3K/Akt signaling pathways, and are associated with diabetes, obesity, and cardiovascular diseases. The overexpression of circulating miR-29a-5p, miR-126-3p, miR-221-3p, and miR-486-5p may explain the increased risk of obesity and diabetes associated with macrosomia. The use of dried blood spots from newborn screening cards to quantify miRNAs expression levels could be an early and minimally invasive predictive tool for these metabolic alterations.
Asunto(s)
MicroARN Circulante/metabolismo , Macrosomía Fetal/diagnóstico , Regulación del Desarrollo de la Expresión Génica , Enfermedades Metabólicas/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adulto , Estudios de Casos y Controles , MicroARN Circulante/sangre , Biología Computacional , Pruebas con Sangre Seca , Estudios de Factibilidad , Femenino , Macrosomía Fetal/sangre , Macrosomía Fetal/metabolismo , Redes Reguladoras de Genes , Humanos , Recién Nacido de Bajo Peso/sangre , Recién Nacido , Masculino , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/prevención & control , Tamizaje Neonatal/métodos , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/prevención & control , Medición de Riesgo/métodosRESUMEN
Context: Differential expression profiles of microRNAs have been reported in human obesity suggesting a miRNAs role in the development of obesity and associated disorders. Objective: To review circulating microRNAs (c-miRNAs) dysregulated in human obesity and to predict their possible target genes. Methods: We performed a systematic review on PubMed database (PROSPERO, CRD42017077742) for original works on c-miRNAs and human obesity and recorded c-miRNAs with differential expression profiles. Potential target genes and metabolic pathways for dysregulated miRNAs with at least two independent reports were searched using bioinformatic tools. Results: Twenty-two c-miRNAs are overexpressed, nine underexpressed and two c-miRNAs dysregulated in both directions in people with obesity compared to lean controls. Bioinformatic analyses suggest these c-miRNAs target on genes associated with fatty acid metabolism and PI3k/Akt pathway. Conclusion: Literature records 33 c-miRNAs confirmedly dysregulated in human obesity. Their predicted target genes are involved in pathways that could explain the development of obesity and its comorbidities. Further research will clarify the role of these miRNAs on metabolic diseases and their usefulness for the prognosis, prevention and treatment of obesity.
Asunto(s)
MicroARN Circulante/genética , Metabolismo de los Lípidos/genética , Obesidad/diagnóstico , Obesidad/genética , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , MicroARN Circulante/sangre , MicroARN Circulante/clasificación , Biología Computacional/estadística & datos numéricos , Ácidos Grasos/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Redes y Vías Metabólicas/genética , Obesidad/sangre , Obesidad/fisiopatología , Fosfatidilinositol 3-Quinasas/sangre , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/sangre , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Birth weight is an early predictor for metabolic diseases and microRNAs (miRNAs) are proposed as fetal programming participants. To evaluate the use of dried blood spots (DBS) on newborn screening cards (NSC) as a source of analyzable miRNAs, we optimized a commercial protocol to recover total miRNA from normal birth weight (NBW, n = 17-20), low birth weight (LBW, n = 17-20) and high birth weight (macrosomia, n = 17-20) newborns and analyzed the relative expression of selected miRNAs by stem-loop RT-qPCR. The possible role of miRNAs on the fetal programming of metabolic diseases was explored by bioinformatic tools. The optimized extraction of RNA resulted in a 1.2-fold enrichment of miRNAs respect to the commercial kit. miR-33b and miR-375 were overexpressed in macrosomia 9.8-fold (p < 0.001) and 1.7-fold, (p < 0.05), respectively and miR-454-3p was overexpressed in both LBW and macrosomia (19.7-fold, p < 0.001 and 10.8-fold, p < 0.001, respectively), as compared to NBW. Potential target genes for these miRNAs are associated to cyclic-guanosine monophosphate (cGMP)-dependent protein kinase (PKG), mitogen-activated protein kinase (MAPK), type 2 diabetes, transforming growth factor-ß (TGF-ß)and Forkhead box O protein (FoxO) pathways. In summary, we improved a protocol for analyzing miRNAs from NSC and provide the first evidence that birth weight modifies the expression of miRNAs associated to adult metabolic dysfunctions. Our work suggests archived NSC are an invaluable resource in the search for fetal programming biomarkers.