Circulating microRNA differ in the early stages of insulin resistance in prepubertal children with obesity

Authors: SANTOS, DIANA - University Of Coimbra; PORTER-GILL, PATRICIA - Arkansas Children'S Hospital; GOODE, GRACE - University Arkansas For Medical Sciences (UAMS); DELHEY, LEANNA - University Arkansas For Medical Sciences (UAMS); SØRENSEN, ANJA ELAINE - Roskilde University; ROSE, SHANNON - University Arkansas For Medical Sciences (UAMS); BØRSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS); DALGAARD, LOIUSE - Roskilde University; CARVALHO, EUGENIA - University Of Coimbra

Submitted to: Life Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2022
Publication Date: 11/28/2022
Citation: Santos, D., Porter-Gill, P., Goode, G., Delhey, L., Sørensen, A., Rose, S., Børsheim, E., Dalgaard, L.T., Carvalho, E. 2022. Circulating microRNA differ in the early stages of insulin resistance in prepubertal children with obesity. Life Sciences. https://doi.org/10.1016/j.lfs.2022.121246.
DOI: https://doi.org/10.1016/j.lfs.2022.121246

Interpretive Summary: Pediatric overweight and obesity are a major public health concern. Being overweight or obese early in life increases the risk of additional future health problems. By discovering disturbances early, preventive interventions can be implemented. Thus, it would be important to identify markers that can be assessed to help evaluate the risk of metabolic disturbances. The microRNAs (miRNAs) are small molecules that regulate the type and amount of proteins a cell is making. Since miRNAs display specific characteristics that make them useful disease biomarkers, they have attracted scientific interest. In the current study, investigators studied the miRNA profile in blood samples from 63 children 5-9 years of age of varying weight status to assess if the miRNA profile differed between children depending on their weight status and sensitivity to the insulin hormone. For the data analyses, children were divided into groups with either normal weight (n = 20, NW) or with overweight/obesity (n = 43, OW/OB), calculated using the children's height and weight relative to reference values. The OW/OB group was further divided into insulin sensitive or metabolically healthy obese (n = 26) and insulin resistant or metabolically unhealthy obese (n = 17), based on their glucose and insulin concentrations in blood. While no differences were observed in fasting plasma glucose levels, serum insulin concentrations were significantly elevated in the OW/OB compared to the NW group. Of 188 screened miRNAs, 11 were differentially expressed between NW and OW/OB groups. Validation confirmed differences in circulating levels of certain miRNAs between the NW and OW/OB groups. Similarly certain miRNAs were correlated with the degree of insulin resistance. The investigators found evidence of alterations that occur early in childhood and these findings may help in guiding targeted prevention of obesity related disturbances at an early stage.

Technical Abstract: Increasing childhood obesity escalates the risk for obesity complications, including insulin resistance. Circulating microRNAs (miRNAs) have been suggested as biomarkers and predictors of obesity and insulin resistance. We aimed to identify a miRNA profile that reflects insulin resistance in prepubertal children with obesity before the occurrence of obesity related complications. Plasma miRNAs were measured in prepubertal children (n = 63, 5-9 years) using TaqMan 36 Advanced miRNA Human Serum/Plasma plates and then validated by RT-qPCR. Subjects were divided into normal weight (n=20, NW) and overweight or obese (n = 43, OW/OB) according to their BMI z-scores. The OW/OB group was further divided into insulin sensitive or metabolically healthy obese (n = 26, MHO) and insulin resistant or metabolically unhealthy obese (n = 17, MUO), according to the HOMA-IR. While no differences were observed in fasting plasma glucose levels, serum insulin levels were significantly elevated in the OW/OB compared to the NW group. Of 188 screened miRNAs, eleven were differentially expressed between NW and OW/OB groups. Validation confirmed increased circulating levels of miR-146a-5p and miR-18a-5p in the OW/OB group, which correlated with the BMI z-score. Interestingly, miR-146a-5p was also correlated with the HOMA-IR index. While only miR-18a-5p was upregulated in the OW/OB children independently of their degree of insulin sensitivity, miR-146-5p, miR-423-3p and miR-152-3p were associated with insulin resistance. The present study provides evidence of alterations that occur early in prepubertal obesity that are crucial for targeted prevention or prompt precision therapeutic interventions.