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-κB α (IκB-α) and IκB-β. 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. IntroductionExcessive fatty acid mobilization found in abdominal obesity is a key mediator of many obesity-related metabolic complications, including insulin resistance (1-3). A high rate of fatty acid availability and subsequent uptake by skeletal muscle can augment intramuscular triglyceride (IMTG) accumulation (1, 3), and there is a strong correlation between IMTG concentration and the severity of insulin resistance in obese subjects and individuals with type 2 diabetes (4, 5). Recent studies, however, clarify that IMTG accumulation likely does not directly affect insulin action (6-9) but instead appears to be a biologically inert reservoir for fatty acids that can serve as a marker for high rates of fatty acid flux into muscle. Alternatively, it is now apparent that highly bioactive fatty acid metabolites, such as diacylglycerol and ceramide (and not IMTG), play a pivotal role in mediating fatty acid-induced insulin resistance in muscle (10-12). Considering the negative effects of diacylglycerol and ceramide on insulin action, we propose what we believe to be a novel hypothesis that, under conditions of high fatty acid flux, enhancing the partitioning of fatty acids entering the muscle toward IMTG synthesis will reduce the formation and accumulation of more damaging fatty acid metabolites within the cell, thereby improving insulin action (8).

Can resveratrol help to maintain metabolic health?

“…Despite this fat accumulation PLIN2/5 overexpression did not result in the development of lipid-induced insulin resistance, suggesting that storage of lipid droplets in skeletal muscle does not need to hamper insulin sensitivity when also the machinery for proper lipid droplet dynamics is enhanced (58,59) . Consistently, it was previously shown that acute exercise is able to overcome lipid-induced insulin resistance by enhancing the capacity to store TAG in muscle (60) . Whether the effect of resveratrol on IMCL content in human subjects is also due to PGC1α-induced activation of the lipid droplet gene programme and results in efficient and safe storage of lipid in muscle is a tempting speculation, but needs further investigation.…”

Comparison of Substrate Oxidation and Energy Expenditure During Acute Aerobic Exercise With Moderate and High Intensity in Patients With Type 2 Diabetes

“…Also, Re-esterified for example, the Re-Esterified triglycerides decreases (24) and the amount of adipose tissue blood flow increases which eventually causes the increase of the availability of fatty acids in plasma (23). Parallel to this study, Schenk et al (2007) have shown that the fat oxidation of the physical activity improves the disorders of fatty acid-induced insulin sensitivity (5).…”

“…Also, resistance to insulin induced by fatty acids is largely determined by extra fatty acid detachment in muscle cells for intracellular fatty acid metabolites' saving, oxidation or aggregation (27)(28)(29). Resistance to insulin induced of fat increase in diabetic patients can decrease by such a physical activity in which fat oxidation occurs in a high rate (5,30,31).…”

“…Previous studies have shown that fat oxidation and absorption in type 2 diabetic patients' skeletal muscles has decreased in post-absorptive state (3) and during β-adrenergic stimulation (3,4). Schenk et al (2007) revealed that fat oxidation induced from physical exercise improves fatty acids induced insulin sensitivity disorders (5). Fat and carbohydrates are main sources to use during rest and physical activity which may change their contribution in providing energy considering the time and intensity of that physical activity, previous fitness, ingredients used in the days before activity, muscle glycogen, exercise and environmental conditions (6).…”

Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle

“…For example, DGAT1 has broader substrate specificity (57) and an apparently higher K m than DGAT2 (51) and may play a greater role in protecting cells from toxicity of lipids (38). Additionally, increased DGAT1 activity has been implicated in the "exercise paradox" in which increased muscle TG is associated with increased insulin sensitivity (39,47). DGAT2, on the other hand, may be more important in the esterification of fatty acids of de novo synthesis (42,51) rather than in protecting cells from lipid-mediated cytotoxicity.…”