Our laboratory has previously shown that the humanized murine model P465L‐PPARγ developed hepatic steatosis after 4 months on an HFD5 in the same way that P467L human carriers do.21 Here, we dissect the mechanisms leading to this phenotype in vivo and propose that the P465L‐PPARγ mutation increases susceptibility to fatty liver through a mechanism that involves a partial deficiency of the transactivation capacity of PPARα. Here, PPARA is linked to fatty liver disease.