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A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis
Aina Lluch, … , Sara C. Kozma, Francisco J. Ortega
Aina Lluch, … , Sara C. Kozma, Francisco J. Ortega
Published June 23, 2022
Citation Information: JCI Insight. 2022;7(14):e150461. https://doi.org/10.1172/jci.insight.150461.
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Research Article Metabolism Therapeutics

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

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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.

Authors

Aina Lluch, Sonia R. Veiga, Jèssica Latorre, José M. Moreno-Navarrete, Núria Bonifaci, Van Dien Nguyen, You Zhou, Marcus Höring, Gerhard Liebisch, Vesa M. Olkkonen, David Llobet-Navas, George Thomas, Ruth Rodríguez-Barrueco, José M. Fernández-Real, Sara C. Kozma, Francisco J. Ortega

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Figure 5

Impact of LY on obese mice.

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Impact of LY on obese mice.
(A) Pipeline diagram for setting #2 and weig...
(A) Pipeline diagram for setting #2 and weight-loss curve in diet-induced obese (DIO) mice maintained on a high-fat and high-sucrose western diet (WD), or WD plus oral gavage of LY (DIO + LY). (B–D) Whole body weight and measures taken for depots of SAT and VAT, and brown adipose tissue (BAT) upon sacrifice confirm weight reduction. (E–G) H&E staining in SAT, distribution of adipocyte sizes (%), and total adipocyte area in DIO and DIO + LY mice. See also Supplemental Figure 7, C–E. (H and I) Circulating TG and cholesterol taken in 6-hour fasted mice upon sacrifice. (J) Representative 200× images of H&E staining in liver samples. (K) Quantification of the lipid content (TG and total cholesterol) in DIO and DIO + LY livers. (L–N) Real-time PCR of gene candidates from setting #1 were assessed in liver (L), SAT (M), and VAT samples (N). Data are presented as mean ± SEM. n = 4 for the DIO-control group, and n = 3 in the DIO + LY group. Statistical significance was determined by Fisher’s exact t test. *P < 0.05, **P < 0.01.

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