Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Metabolism Therapeutics

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

  • Text
  • PDF
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

×

Figure 1

Physiological effects of LY on mice undergoing a high-fat diet.

Options: View larger image (or click on image) Download as PowerPoint
Physiological effects of LY on mice undergoing a high-fat diet.
(A) Pipe...
(A) Pipeline diagram for setting #1 and weight gain curve of mice under normal chow (NC) and high-fat diet (HFD) plus vehicle, and HFD plus oral gavage (25 mg/kg/12 h) with the S6K1 inhibitor LY2584702 tosylate (HFD + LY). (B and C) Body weight measures taken just before sacrifice, and weight of inguinal s.c. (SAT) and epididymal visceral (VAT) depots of white adipose tissue (n = 5/7/7 for NC, HFD, and HFD + LY, respectively). (D and E) Circulating triglycerides (TG) (D) and cholesterol at fasting (n = 4/5/6) and measures of glucose during an i.p. insulin tolerance test (ITT) and in 6-hour fasted mice (E) (n = 4/7/7). (F–H) Representative images of H&E staining in SAT, distribution of adipocyte sizes (%), and total adipocyte area in NC, HFD and HFD + LY mice (n = 2/3/3). Scale bar: 100 nm. (I) Representative 200× images of H&E staining in liver samples. (J) Quantification of the lipid content (TG and total cholesterol) of NC, HFD, and HFD + LY livers (n = 4/5/5). Data are presented as mean ± SEM using 2-way ANOVA followed by the Šidák’s correction, and adjusted P values for repeated measures are provided in weight gain curves (i.e., HFD versus NC, and HFD + LY versus HFD). The Dunnett’s multiple-comparison procedure was applied to the rest of measurements, in which nontreated HFD-fed mice served as the reference group. *P < 0.05, **P < 0.01.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts