Journal Article

Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels

Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain], ERDF, A way of making Europe, grant PID2021-122116OB-100 (M.V.-C. and X.P.) funded by MCIU/AEI/https://doi.org/10.13039/501100011033, Jurado-Aguilar, Javier, Wahli, Walter, Peyman, Mona, Palomer, Xavier, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) ; Instituto de Salud Carlos III [Madrid] (ISCIII), Montori-Grau, Marta, Institut de Biomedicina de la Universitat de Barcelona - Institute of Biomedicine of the University of Barcelona (IBUB) ; Universitat de Barcelona (UB), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG) ; Swiss Institute of Bioinformatics [Lausanne] (SIB) ; Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Universitat de Barcelona (UB), Vázquez-Carrera, Manuel, ToxAlim (ToxAlim) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse

2025

Overview

Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15 -/-mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15 -/-mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15 -/-mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15 -/-mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.

• Publisher: Springer Verlag,CCSD,Springer International Publishing,Springer Nature B.V
• Subject: Animals / Binding / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cell Biology / Cell Line / Cell Nucleus - drug effects / Cell Nucleus - metabolism / cytokines / diet / Diet, High-Fat - adverse effects / genes / Glucose / Glucose metabolism / Glucose tolerance / Growth Differentiation Factor 15 - genetics / Growth Differentiation Factor 15 - metabolism / Growth factors / Hepatocyte growth factor / High fat diet / Humans / Insulin / Insulin receptor substrate 1 / insulin receptor substrate proteins / Insulin resistance / Leptomycin B / Life Sciences / ligands / Lipids / Male / metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Muscle Fibers, Skeletal - drug effects / Muscle Fibers, Skeletal - metabolism / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / Myotubes / Nuclear transport / oleic acid / Original / Original Article / palmitates / Palmitates - pharmacology / Palmitic acid / Phosphorylation / physiological transport / Plasminogen Activator Inhibitor 1 - genetics / Plasminogen Activator Inhibitor 1 - metabolism / Plasminogen activator inhibitors / Protein transport / Proteins / signal transduction / Signal Transduction - drug effects / Skeletal muscle / Smad protein / Smad3 protein / Smad3 Protein - metabolism / Stat3 protein / transactivators
• ISBN: 0014084084000