The FTO (fat mass- and obesity-associated) gene variant is an established obesity-susceptibility locus. FTO protein is a nucleic acid demethylase and FTO genetic variants form long-range functional connections with IRX3, which regulates fat mass and metabolism in humans. From our previous results, we found FTO regulates the metabolism of triglyceride in adipocytes through demethylating Angptl4 (angiopoietin-like protein 4) mRNA in mice. We hypothesized that the FTO genetic variants regulate ANGPTL4 abundances in human adipose tissues and affect the outcome after bariatric surgery.

We recruited 188 obesity subjects with body mass indices (BMI)>35kg/m² and 102 non-obese subjects with BMI<30kg/m² from the OCEAN registry between 2011 and 2014. The distribution of FTO variants rs9939609 among participates was 73.79% TT, 23.79% AT, and 2.41% AA. The subjects with FTO variants AA or AT were correlated with higher BMI than those with FTO variants TT. The serum ANGPTL4 levels were significantly higher in obese subjects and positively correlated with the presence of FTO AA or AT haplotype. Of these participates, 84 obese subjects underwent bariatric surgery and adipose Angptl4 expressions were analyzed. The adipose Angptl4 mRNA levels and protein abundances were correlated with FTO AA or AT haplotype. The magnitude of excess body weight reduction 2 years after bariatric surgery was correlated with the adipose ANGPTL4 protein levels.

Adipose ANGPTL4 abundances were affected by the presence of FTO obesity risk haplotype and correlated with excess weight loss percentage after bariatric surgery. These data signify the critical role of FTO variants and adipose ANGPTL4 in fatty acid metabolism and bariatric outcomes in humans.