Does Endurance Training Protect From Lipotoxicity?

Mechanisms of lipid-induced insulin resistance in skeletal muscle. Lipolysis of plasma triglycerides (TG) by lipoprotein lipase (LPL) increases FFAs, including saturated fatty acids (SFA), which are taken up by fatty acid transporters (Fatp1/CD36) and activated to fatty acyl-CoA (FA-CoA) by acyl-CoA synthase. Substrate competition postulates that lipid oxidation in the tricarboxylic acid (TCA) cycle raises the NADH/NADH⁺ and acetyl-CoA/CoA ratios, which inhibits pyruvate dehydrogenase (PDH) and subsequently phosphofructokinase (PFK) and hexokinase II (HKII). Glucose-6-phosphate (G6P) would inhibit glucose uptake and feed glycogen synthesis via glycogen synthase (GSK). Substrate signaling involves the lipid intermediate DAG arising from triglyceride synthesis via glycerol phosphate synthase (GPAT) and DAG acyltransferase (DGAT) or from lipolysis via adipose tissue triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). Certain DAG species activate novel PKC isoforms and inhibit insulin receptor substrate-1 (IRS1) signaling. Ceramides are synthesized via serine palmitoyl transferase (SPT), which is also transcriptionally activated by inhibitory-κB kinase (IKK) and ceramide synthase (CS) and in turn inhibit Akt signaling. Inhibition of insulin signaling will inhibit glucose transporter-4 (GLUT4) recruitment and thereby decrease glucose transport/phosphorylation. In this model, glycogen synthesis will decrease in turn and/or as a result of lower phosphorylation (p) of glycogen synthase kinase-3β (GSK3β), which would lead to lower glycogen synthase (GS) activity. AMPK, AMP-activated protein kinase.