Inhibition of AKT or mTOR molecules mitigates obesity-associated metabolic disorders in Riz1 mice with obesity

The deficiency of the tumor suppressor factor RIZ1 can lead to obesity with activation of the V-Akt murine thymoma viral oncogene homolog (PKB) (AKT)/mechanistic target of rapamycin (mTOR) pathway. The aim of this study was to elucidate the role of RIZ1 in obesity through the inhibition of the AKT or mTOR pathway. Riz1 knockout mice (KO) were randomly treated with either the AKT inhibitor afuresertib or the mTOR inhibitor rapamycin. The survival rate in the afuresertib-treated group was lower than that in the rapamycin-treated group. Both afuresertib and rapamycin significantly reduced weight gain and hepatic steatosis in KO mice. Metabolic cage analysis of inhibitor-treated KO mice revealed increased oxygen consumption and enhanced lipid utilization. The inhibitor-treated mice exhibited improved glucose regulation and enhanced insulin sensitivity, which was accompanied by reduced blood glucose and insulin levels. Serum triglyceride levels were significantly reduced in inhibitor-treated groups. Mice treated with the inhibitors exhibited significantly suppressed AKT/mTOR signaling pathway in liver, muscle, and adipose tissues, as well as downregulation of genes associated with energy and lipid metabolism (L-Fabp, Pparα/γ, Ubiad1, Cyp4a12). These findings demonstrate that inhibition of either the AKT or mTOR molecules mitigates obesity and metabolic dysregulation in Riz1^-/- mice, highlighting the critical role of the RIZ1/AKT/mTOR axis in maintaining metabolic homeostasis.