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Background  Genome-wide association studies have identified variants within the  FTO  (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in  FTO  directly affect human adipocyte function through targeting  IRX3  and  IRX5  and thermogenesis regulation.    Aim  We addressed the relevance of this proposed  FTO-IRX  pathway in adipose tissue (AT) of children.    Results  Expression of  IRX3  was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of  IRX3  and  IRX5  with the presence of the  FTO  risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that  IRX3  expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in  UCP1 -negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI,  IRX3  expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children.    Conclusion  One interpretation of our observation of  FTO  risk variants linked to  IRX3  expression and adipocyte size restricted to lean children, along with the decreased  IRX3  expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.

plos one

FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?