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.