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

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 diet-induced 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. © 2017 BioFactors, 43(5):718-730, 2017.

Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria.

In the heart, a nutritional state (fed or fasted) is characterized by a unique energy metabolism pattern determined by the availability of substrates. Increased availability of acylcarnitines has been associated with decreased glucose utilization; however, the effects of long-chain acylcarnitines on glucose metabolism have not been previously studied. We tested how changes in long-chain acylcarnitine content regulate the metabolism of glucose and long-chain fatty acids in cardiac mitochondria in fed and fasted states. We examined the concentrations of metabolic intermediates in plasma and cardiac tissues under fed and fasted states. The effects of substrate availability and their competition for energy production at the mitochondrial level were studied in isolated rat cardiac mitochondria. The availability of long-chain acylcarnitines in plasma reflected their content in cardiac tissue in the fed and fasted states, and acylcarnitine content in the heart was fivefold higher in fasted state compared to the fed state. In substrate competition experiments, pyruvate and fatty acid metabolites effectively competed for the energy production pathway; however, only the physiological content of acylcarnitine significantly reduced pyruvate and lactate oxidation in mitochondria. The increased availability of long-chain acylcarnitine significantly reduced glucose utilization in isolated rat heart model and in vivo. Our results demonstrate that changes in long-chain acylcarnitine contents could orchestrate the interplay between the metabolism of pyruvate-lactate and long-chain fatty acids, and thus determine the pattern of energy metabolism in cardiac mitochondria.

Inhibition of mouse skin tumor promotion by adriamycin and daunomycin in combination with verapamil or palmitoylcarnitine.

The anti-cancer drugs Adriamycin (ADR) and Daunomycin (DAU) alone were unable to inhibit the promotion of skin papillomas by repeated applications of 8.5 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mice. Pretreatments with 50 micrograms of ADR also failed to alter the tumor-promoting activities of smaller doses of TPA. Therefore, the effects of the anthracycline antibiotics on skin tumor promotion were evaluated in combination with the Ca2+ antagonist verapamil (VRP) and the protein kinase C (PKC) inhibitor palmitoylcarnitine (PC), compounds known to circumvent drug resistance. When applied simultaneously with each promotion treatment with 8.5 nmol of TPA, 2.5 mg of VRP inhibited the number of papillomas/mouse by 26%. But the combination of VRP + 50 micrograms of ADR or DAU inhibited the yields of papillomas by 50 or 47%, respectively, suggesting that VRP was required to reveal the antitumor-promoting activities of otherwise ineffective drugs. Similarly, the promotion of skin tumors by TPA was inhibited synergistically by the combinations of 2 mumol of PC + 50 micrograms of ADR or DAU. For instance, ADR and DAU had no effects alone but inhibited the incidence of skin papillomas by 78 and 86%, respectively, in the presence of PC, a compound which alone inhibited the tumor incidence by only 44%. The results indicate that ADR and DAU are effective against the promoting component of skin carcinogenesis only if they are applied in combination with Ca2+ antagonists or PKC inhibitors at a time when they can inhibit the early biochemical effects induced by TPA.