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

Area of Science:

• Molecular Endocrinology
• Metabolic Syndrome
• Skeletal Muscle Physiology

Background:

• Nuclear growth differentiation factor 15 (GDF15) normally inhibits SMAD complex binding to DNA.
• The specific stimuli regulating nuclear GDF15 levels and subsequent pathway activation remain largely unknown.
• Skeletal muscle is a primary site for insulin-stimulated glucose uptake, making it crucial for metabolic health.

Purpose of the Study:

• To investigate if saturated fatty acids (FA), particularly palmitate, influence nuclear GDF15 levels.
• To determine the effect of palmitate on the SMAD3 pathway activation in human skeletal myotubes and mouse muscle.
• To elucidate the role of GDF15 in high-fat diet-induced insulin resistance in skeletal muscle.

Main Methods:

• Utilized human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15 knockout mice.
• Administered standard (STD) and high-fat diets (HFD) to mice.
• Assessed GDF15 expression and localization, SMAD3 activation, PAI-1 levels, and glucose tolerance.

Main Results:

• Palmitate increased GDF15 expression but decreased its nuclear levels in human myotubes, an effect blocked by leptomycin B.
• Palmitate-induced reduction in nuclear GDF15 correlated with increased SMAD3 and PAI-1 (SERPINE1) expression.
• Gdf15-deficient mice on HFD exhibited worsened glucose intolerance, elevated skeletal muscle SMAD3 and PAI-1, reduced HGFα, activated STAT3, and decreased IRS-1.

Conclusions:

• Palmitate actively reduces nuclear GDF15 levels in skeletal muscle cells.
• This reduction initiates a SMAD3-PAI-1 signaling cascade, contributing to insulin resistance.
• GDF15 deficiency exacerbates high-fat diet-induced metabolic dysfunction, highlighting GDF15's protective role against diet-induced insulin resistance.