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

Lluch, Aina, Veiga, Sonia R., Latorre, Jèssica, Moreno-Navarrete, José M., Bonifaci, Núria, Dien Nguyen, Van, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Höring, Marcus, Liebisch, Gerhard, Olkkonen, Vesa M., Llobet-Navas, David, Thomas, George, Rodríguez-Barrueco, Ruth, Fernández-Real, José M., Kozma, Sara C. and Ortega, Francisco J. 2022. A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis. JCI Insight 7 (14) , e150461. 10.1172/jci.insight.150461

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Abstract

The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired 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 in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	25 October 2022
Date of Acceptance:	15 June 2022
Last Modified:	21 May 2023 19:32
URI:	https://orca.cardiff.ac.uk/id/eprint/153762

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