Acute and long‐term administration of palmitoylcarnitine induces muscle‐specific insulin resistance in mice

Abstract

Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of dietinduced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity.

Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific Insulin Sensitivity

“…In the present study, fasted-state long-chain acylcarnitine levels were significantly decreased in both experimental models, with adipose and muscle tissue insulin resistance, compared to healthy controls. This decrease indicates on fasting hyperinsulinemiainduced inhibition of CPT1-mediated long-chain acylcarnitine synthesis (7,27,28). These observations are in line with a study by Schooneman et al, showing that the insulin sensitivity index did not correlate with fasted levels of plasma acylcarnitines, and improvement in insulin sensitivity in overweight individuals resulted in an increase in fasted state levels of individual acylcarnitine species (C2, C4OH, C10, C14:1, C16, C18:1) (29).…”

“…The concentrations of acylcarnitines in the plasma samples were determined with a UPLC MS/MS method using a Waters Acquity liquid chromatography system and Waters Quattro Micro or Waters Xevo TQ-S mass spectrometer, as previously described (17,27).…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…The shift towards long‐chain acylcarnitine accumulation is a result of unbalanced acylcarnitine synthesis and mitochondrial oxidation rates, which leads to accumulation of long‐chain acylcarnitines in mitochondria—often referred to in the literature as incomplete FAO . In this case, the highest concentrations of long‐chain acylcarnitines are found in the mitochondrial inner membrane and the intermembrane space, but long‐chain acylcarnitines can also escape from mitochondria and inhibit the insulin signalling cascade upstream of protein kinase b (Akt) phosphorylation, favouring FA metabolism at the expense of glucose/pyruvate metabolism . Meanwhile, in cardiac mitochondria, long‐chain acylcarnitines inhibit pyruvate and lactate metabolism even at physiological concentrations .…”

Defining lipid mediators of insulin resistance: controversies and challenges

“…Pharmacological reduction of acylcarnitine content in a mouse model of IR has been reported to recover insulin sensitivity and reduce blood glucose levels (Liepinsh et al 2016). An accompanying study, which heightened acylcarnitine content in mice through both acute and long-term administration of palmitoylcarnitine, saw the consequential induction of muscle-specific IR (Liepinsh et al 2017). Regulation of metabolic flexibility, production of reactive oxygen species and inhibition of insulin signalling have all been suggested as mechanisms linking acylcarnitines with IR (Muoio et al 2012, Aguer et al 2015, Liepinsh et al 2017, although it is still unclear to what extent acylcarnitines have a primary role in the induction of IR.…”