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

Publisher Copyright: © 2017 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular BiologyAcylcarnitine 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.publishersversionPeer reviewe

Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ‑Butyrobetaine Hydroxylase

γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)­propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC₅₀ values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design

Pintavedenoton suhteen kriittisimmät väyläosuudet liikenteen ja väylänpidon kannalta

<i>N</i>-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of <i>E. coli</i> leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure–activity relationship analysis. Enzymatic assays revealed that <i>N</i>-leucinyl benzenesulfonamides display remarkable selectivity for <i>E. coli</i> leucyl-tRNA synthetase compared to <i>S. aureus</i> and human orthologues. The simplest analogue of the series, <i>N</i>-leucinyl benzenesulfonamide (R = H), showed the highest affinity against <i>E. coli</i> leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, <i>E. coli</i> ATCC 25922), which renders it as a promising template for antibacterial drug discovery