An Alternatively Translated Isoform of PPARG Suggests AF-1 Domain Inhibition as an Insulin Sensitization Target

Genetic screens were performed across PPARG to study how disruptive mutations across the full coding sequence affect function. An alternative translational start site in PPARG generates a truncated isoform, peroxisome proliferator-activated receptor γ (PPARγ) M135, which lacks the N-terminal activation function 1 (AF-1) domain and shows increased agonist-induced transactivation of target genes. In human carriers of rare PPARG variants, AF-1 domain-disrupting genetic variants increase agonist-induced PPARγ activity and decrease metabolic syndrome severity. Targeting the AF-1 domain is a potential therapeutic strategy for insulin sensitization.