Acylcarnitines: potential implications for skeletal muscle insulin resistance

Abstract

Insulin resistance may be linked to incomplete fatty acid b-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid b-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitateinduced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short-or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid b-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.-Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono-Moore, K., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., Harper, M.-E. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 29, 336-345 (2015). www.fasebj.org

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Although typically short‐lived, LCAC accumulate in states of inefficient fatty acid oxidation (FAO), which may be attributed to (1) defects in mitochondrial FAO enzymes or (2) increased FAO relative to tricarboxylic acid (TCA) flux; this leads to a bottleneck of carbon substrates at the TCA cycle 53, 54. Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57.…”

“…Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57. Regardless of the precise cause, LCAC are transported out to the plasma, where they are subsequently metabolized in several tissues (especially skeletal muscle, liver, and heart) or excreted in urine or bile 52, 56, 57.…”

“…When elevated, plasma LCAC reflect underlying mitochondrial dysfunction and dysregulated carbohydrate/fatty acid metabolism, which have both been recognized as viable therapeutic targets in HF 52, 56, 59, 60. Similarly, elevated plasma LCAC has been used for decades as a screening measure for genetic deficiencies of FAO enzymes 59.…”

“…First, by activating cyclooxygenase‐2 signaling and increasing interleukin‐6 release, LCACs may promote local skeletal muscle inflammation and systemic inflammation, which are both pathophysiological targets in HF 63, 64, 65, 69. Second, LCACs stimulate reactive oxygen species production and promote cellular stress through activation of c‐Jun amino‐terminal kinase, p38 mitogen‐activated protein kinase, and the apoptotic caspase‐3 protein 56, 63. Third, LCACs may promote malignant arrhythmias by (1) modulating deactivation kinetics of voltage‐gated potassium channels and (2) broadly increasing intracellular calcium concentrations by promoting net calcium efflux from the sarcoplasmic reticulum 66, 67, 68.…”

“…Third, LCACs may promote malignant arrhythmias by (1) modulating deactivation kinetics of voltage‐gated potassium channels and (2) broadly increasing intracellular calcium concentrations by promoting net calcium efflux from the sarcoplasmic reticulum 66, 67, 68. Last, LCACs may not only reflect, but also exacerbate IR by inducing serine phosphorylation of insulin receptor substrate 1 56. Through these actions and potential downstream effects on the cyclic guanosine monophosphate/protein kinase G pathway, elevated LCACs may reflect, promote, or exacerbate myocardial and peripheral pathologies contributing to the HF phenotype (Figure).…”