RESUMO
This study explored circulating miRNAs and target genes associated with metabolic syndrome (MetS) and cardiometabolic risk in obese patients. Small-RNA sequencing was used to assess the peripheral blood miRNome of 12 obese subjects (6 MetS and 6 non-MetS). Differentially expressed miRNAs and target genes were further analyzed by qPCR in a larger sample of obese patients (48 MetS and 32 non-MetS). miRNA:mRNA interactions were studied using in silico tools. miRNome analysis identified 10 downregulated miRNAs in MetS compared to non-Met patients (p < 0.05). In silico studies revealed three miRNAs (miR-155, miR-181a, and let-7a) and their predictive targets (CCAAT/enhancer-binding protein beta-CEBPB, KRAS proto-oncogene, GTPase-KRAS and suppressor of cytokine signaling 1-SOCS1) with a potential role in the insulin receptor signaling pathway. miR-155 expression was reduced and CEBPB mRNA levels were increased in MetS patients (p < 0.05), and these effects were correlated with the number of MetS diagnostic criteria (p < 0.05). Increased HOMA-IR (>7.6) was associated with low miR-155 levels, high CEBPB expression, and serum hsCRP (p < 0.05). miR-155 was negatively correlated with CEBPB, HOMA-IR, and plasma fibrinogen, and positively correlated with serum adiponectin (p < 0.05). Downregulation of circulating miR-155 is associated with insulin resistance, poor glycemic control, and increased MetS-related cardiometabolic risk, and these effects are potentially mediated by interaction with CEBPB.
Assuntos
Doenças Cardiovasculares/sangue , Síndrome Metabólica/sangue , MicroRNAs/metabolismo , Obesidade/complicações , Transdução de Sinais , Adiponectina/sangue , Adulto , Biomarcadores/sangue , Proteína beta Intensificadora de Ligação a CCAAT/sangue , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Simulação por Computador , Feminino , Fibrinogênio/análise , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , MicroRNAs/sangue , Pessoa de Meia-Idade , Obesidade/metabolismo , Proto-Oncogene Mas , Receptor de Insulina/metabolismo , Fatores de Risco , Análise de Sequência de RNARESUMO
Background: Polymorphisms in genes encoding adiponectin (ADIPOQ) and interleukin-6 (IL6) have been associated with adiposity and obese-related phenotypes. This study investigated the relationship of ADIPOQ and IL6 gene polymorphisms with pro-inflammatory and cardiometabolic markers in obese patients. Methods: Anthropometric and body composition parameters were measured in 249 Brazilian subjects (30 to 68 yr). Metabolic and inflammatory markers and adipokines were analyzed in blood samples. ADIPOQ rs2241766 (45 T > G)and IL6 rs1800795 (−174G > C) polymorphisms were analyzed by real-time PCR and PCR-RFLP, respectively. Results: Type 2 diabetes, hypertension, dyslipidemia and increased values of waist circumference, body fat, leptin, fibrinogen, IL-1β, hsCRP and TNFα were related to obesity (p < 0.05). Multiple linear regression analysis showed apositive correlation between BMI and waist circumference, body fat, leptin, fibrinogen, PAI-1, IL-1β, hsCRP and TNFαvalues (p < 0.001) but not with adiponectin. Obese group had altered metabolic status, resistance to leptin andinsulin, and atherogenic and pro-inflammatory profiles. ADIPOQ and IL6 variants were not directely related toobesity, leptin resistance or alterations in cardiometabolic markers. Individuals carrying ADIPOQ 45G allele (TG + GGgenotype) had higher IL-6, IL-1β and TNFα levels than TT genotype carriers (p < 0.05). IL6 -174GG genotype wasassociated with increased IL-1β levels (p = 0.033).Conclusion: Obesity is associated with leptin resistance, cardiometabolic alterations and a pro-inflammatory status.Our results are suggestive that ADIPOQ and IL6 polymorphisms contribute to cardiometabolic risk in obese individuals.