4‐Hydroxyisoleucine ameliorates fatty acid‐induced insulin resistance and inflammatory response in skeletal muscle cells

Abstract

The 4‐Hydroxyisoleucine (4‐HIL), an unusual amino acid isolated from the seeds of Trigonella foenum‐graecum was investigated for the metabolic effects to ameliorate free fatty acid‐induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin stimulated‐ glucose uptake and ‐translocation of glucose transporter 4 (GLUT4) to cell surface. Addition of 4‐HIL strongly prevented this inhibition. We then examined insulin signaling pathway, where 4‐HIL effectively inhibited the ability of palmitate to reduce insulin‐stimulated phosphorylation of insulin receptor substrate‐1(IRS‐1), protein kinase B (PKB/AKT), AKT substrate of 160 KD (AS160) and glycogen synthase kinase 3β (GSK‐3 β) in L6 myotubes. Moreover, 4‐HIL presented strong inhibition on palmitate‐induced production of reactive oxygen species (ROS) and associated inflammation, as the activation of NF‐κB and, JNK1/2, ERK1/2 and p38 MAPK was greatly reduced. 4‐HIL also inhibited inflammation‐stimulated IRS‐1 serine phosphorylation and restored insulin‐stimulated IRS‐1 tyrosine phosphorylation in presence of palmitate, leading to enhanced insulin sensitivity. These findings suggested that 4‐HIL could inhibit palmitate‐induced, ROS‐associated inflammation and restored insulin sensitivity through regulating IRS‐1 function.