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

Area of Science:

• Biochemistry
• Metabolic Diseases
• Molecular Biology

Background:

• Ribosomal protein S6 kinase 1 (S6K1) is a key downstream effector of mTORC1, regulating lipid homeostasis.
• S6K1 deficiency impairs adipogenesis and reduces fat mass.
• Obesity is linked to dyslipidemia and hepatic steatosis.

Purpose of the Study:

• To investigate the therapeutic potential of S6K1 inhibition in diet-induced obesity.
• To evaluate the effects of a specific S6K1 inhibitor (LY2584702 tosylate) on metabolic parameters and gene expression in obese mice.

Main Methods:

• Administration of LY2584702 tosylate to diet-induced obese mice.
• Assessment of fat mass, lipid profiles, liver steatosis, and gene expression.
• Analysis of mTORC1 signaling, epithelial-mesenchymal transition markers, and specific gene expression (Cd36, Lgals1).

Main Results:

• S6K1 inhibition reduced fat mass expansion and ameliorated dyslipidemia and hepatic steatosis.
• Transcriptome-wide gene expression programs related to adipose and liver function were modified.
• Decreased mTORC1 signaling in adipose tissue and increased signaling in the liver were observed.
• Impaired epithelial-mesenchymal transition and reduced expression of Cd36 and Lgals1 were noted in adipose and liver tissues.
• Reduced adipocyte size and improved hepatic lipidomic signatures were achieved.
• Hepatic steatosis and hypertriglyceridemia were improved with both 3-month and 6-week treatment durations.

Conclusions:

• Therapeutic blockage of S6K1 is a promising strategy for combating diet-induced obesity and associated metabolic disorders.
• S6K1 inhibition impacts key pathways involved in lipid metabolism, adipogenesis, and liver function.
• Targeting S6K1 offers a potential therapeutic avenue for managing obesity, hepatic steatosis, and dyslipidemia.