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?

PLoS One. 2016 Aug 25;11(8):e0161739. doi: 10.1371/journal.pone.0161739. eCollection 2016.

Abstract

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.

MeSH terms

  • Adipocytes / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
  • Body Weight / genetics*
  • Case-Control Studies
  • Child
  • Female
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Homeodomain Proteins
  • IRX3 protein, human
  • IRX5 protein, human
  • Transcription Factors
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human

Grants and funding

This work was supported by the German Research Council (DFG) for the Collaborative Research Center "Obesity Mechanisms" CRC1052, the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 (IFB AdiposityDiseases), and the European Community’s 7th Framework Programme project Beta-JUDO n° 279153. Genotyping was facilitated the LIFE Child study (Leipzig Research Center for Civilization Diseases, Universität Leipzig), funded by the European Union, by the European Regional Development Fund (ERFD) by means of the Free State of Saxony within the framework of the excellence initiative.