Tumor suppressor RIZ1 in obesity and the PI3K/AKT/mTOR pathway.

Objective The aim of this study was to investigate the shared molecular pathways of obesity and cancer by exploring the role of RIZ1 in obesity and the phospatidylinositol 3-kinase (PI3K)/V-Akt murine thymoma viral oncogene homolog (PKB) (AKT)/mechanistic target of rapamycin (mTOR) pathway. Methods Male wild type (WT) and Riz1−/− mice (KO) were fed a standard diet (STD) or a high-fat (HF) diet for up to 8 months. These mice were studied for phenotypic and molecular changes. Results Riz1−/− mice gained more weight on a HF diet compared to WT mice, with higher free fatty acid and increased visceral fat. Metabolic cage analysis of Riz1−/− mice showed lower oxygen consumption but no changes in food intake and ambulatory activity. Riz1−/− mice showed impaired glucose regulation but no change in insulin sensitivity. RNA-seq and quantitative RT-PCR analysis found altered expression in certain glycolysis and ATP production genes such as Ubiad1, Atp5g2, and Cyp4a12. The PI3K/AKT/mTOR pathway was activated in the Riz1−/− mice fed a HF diet with higher Akt3 mRNA levels and increased phosphorylation of AKT (Ser473), mTOR, and S6. Conclusions The results identify RIZ1 as an important regulator of both Akt3 transcription and AKT phosphorylation and suggest a role for RIZ1 in HF-induced obesity and the AKT pathway.