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A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis

ABSTRACT: Imbalanced mTORC1-S6K1 engages signalling cascades related to obesity and fatty liver. Here, we set up to assess the therapeutic blockage of the ribosomal protein S6 kinase 1 (S6K1) in diet-induced obese (DIO) mice challenged with LY2584702 (LY) tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. To characterize the ability of LY in counteracting obesity and diet-induced disturbances, DIO male mice were challenged every 12 h by oral gavage with LY in treatments lasting 12 and 4 weeks. We show that diminished S6K1 activity in mice treated with LY hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver performance. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent a decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures, while hypertriglyceridemia and hepatic steatosis were improved in treatments of 12 and 4 weeks. This study provides new insights into the therapeutic intervention of S6K1 signalling, and opens a promising avenue for prevalent metabolic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE193028 | GEO | 2022/08/01

REPOSITORIES: GEO

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