Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance

Abstract

Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid-induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid-induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-kappaB alpha (I kappa B-alpha) and I kappa B-beta. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid-induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.

Figure 1. Timeline of events.

FAT_ox, measurement of whole-body fatty acid oxidation.

Figure 2. Plasma fatty acid concentrations before and during a lipid-plus-heparin infusion.

Values are mean ± SEM (n = 8). *P < 0.05 versus overnight fasted value on day 1 for each group. There were no significant differences between SED and EX, except at 0 hours (P < 0.05).

Figure 3. A single session of exercise prevents lipid-induced insulin resistance.

S_i was measured before (day 1) and during (day 2) a lipid-plus-heparin infusion. Lines connected by dots indicate individual subjects’ day 1 and day 2 S_i levels. Values are mean ± SEM (n = 8). *P < 0.001 versus day 1 within respective trial; ^†P < 0.001 versus day 2 SED.

Figure 4. Exercise enhances the partitioning of fatty acids toward IMTG and reduces the accumulation of fatty acid metabolites in skeletal muscle.

(A) IMTG, (B) diacylglycerol, (C) ceramide, and (D) muscle glycogen concentrations the morning after an overnight infusion of lipid-plus-heparin. Values are mean ± SEM (n = 8). *P < 0.001, ^†P < 0.05, ^#P = 0.056 versus SED. dw, dry weight.

Figure 5. Exercise increases the lipogenic capacity of muscle.

Protein abundance of (A) mGPAT, (B) DGAT1, and (C) SCD1 the morning after an overnight infusion of lipid-plus-heparin. Insets are representative western blots for 2 subjects. Values are mean ± SEM (n = 8). *P < 0.02, **P < 0.01 versus SED.

Figure 6. Skeletal muscle proinflammatory response during a lipid infusion is lower after exercise.

(A) p-JNK, corrected for JNK-1 protein abundance, and protein abundance of IκB-α (B) and IκB-β (C) the morning after an overnight infusion of lipid-plus-heparin. Insets are representative western blots for 2 subjects. Values are mean ± SEM (n = 8). *P < 0.05, **P < 0.001 versus SED.

Figure 7. The ratio of PI3K catalytic subunits to regulatory subunits is higher after exercise.

Protein abundance of the PI3K catalytic subunits (p110β) (A) and regulatory subunits (p85α/β) (B) and (C) the ratio of PI3K catalytic subunits to regulatory subunits the morning after an overnight infusion of lipid-plus-heparin. Insets are representative western blots for 2 subjects. Values are mean ± SEM (n = 8). *P < 0.05 versus SED.

Figure 8. Partitioning of fatty acids toward oxidation during a lipid-plus-heparin infusion is enhanced after exercise.

(A) Whole-body fatty acid oxidation, (B) resting VO₂, (C) RER, and (D) skeletal muscle protein abundance of PGC-1 before and during a lipid-plus-heparin infusion. Inset figures are representative Western blots for 2 subjects. FFM, fat-free mass. Values are mean ± SEM (n = 8). *P < 0.05 versus SED.