Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity

Background Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes. The underlying mechanisms for those differences are still unclear. This study aimed to analyze the whole-blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. Methods Twenty-seven children with OW/OB (10.1 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein-cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers were additionally determined. Total blood RNA was analyzed by 5’-end RNA-sequencing. Results Whole-blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. Thirty-two genes differentially expressed were linked to metabolism, mitochondrial, and immune functions. Conclusions The identified gene expression patterns related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity. Impact A distinct pattern of whole-blood transcriptome profile (RNA-seq) was identified in children with metabolic healthy overweight/obesity (MHO) compared to metabolic unhealthy overweight/obesity (MUO) phenotype. The most relevant genes in understanding the molecular basis underlying the MHO/MUO phenotypes in children could be: RREB1 , FAM83E , SLC44A1 , NRG1 , TMC5 , CYP3A5 , TRIM11 , and ADAMTSL2 . The identified whole-blood transcriptome profile related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity.