Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance

Liepinsh, Edgars; Makrecka-Kūka, Marina; Makarova, Elina; Volska, Kristine; Švalbe, Baiba; Sevostjanovs, Eduards; Grı̄nberga, Solveiga; Kuka, Janis; Dambrova, Maija

doi:10.1016/j.phrs.2015.11.014

Cited by 36 publications

(39 citation statements)

References 36 publications

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“…In previous studies, we hypothesized that LC acylcarnitines are not only markers for incomplete FA oxidation but also active FA metabolites involved in the regulation of energy metabolism . In this study, we confirm this hypothesis through our results indicating that the acute and chronic administration of PC in vivo limits insulin signaling‐induced effects and insulin‐related glucose uptake in muscles.…”

Section: Discussionsupporting

confidence: 85%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 85%

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

et al. 2017

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“…Interestingly, dicarboxylcarnitines and acylcarnitines, plasma branched and aromatic amino acids, phenylalanine, α‐hydroxybutyrate, and ceramides have been associated with cardiovascular risk factors including obesity, insulin resistance, and diabetes mellitus. Different complex mechanisms, including inflammation and stress oxidation, are underlying processes potentially explaining these associations …”

Section: Discussionmentioning

confidence: 99%

Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review

Ruíz-Canela

Hruby

Clish

et al. 2017

JAHA

113

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BackgroundMetabolomics is a promising tool of cardiovascular biomarker discovery. We systematically reviewed the literature on comprehensive metabolomic profiling in association with incident cardiovascular disease (CVD).Methods and ResultsWe searched MEDLINE and EMBASE from inception to January 2016. Studies were eligible if they pertained to adult humans; followed an agnostic and/or comprehensive approach; used serum or plasma (not urine or other biospecimens); conducted metabolite profiling at baseline in the context of examining prospective disease; and included myocardial infarction, stroke, and/or CVD death in the CVD outcome definition. We identified 12 original articles (9 cohort and 3 nested case‐control studies); participant numbers ranged from 67 to 7256. Mass spectrometry was the predominant analytical method. The number and chemical diversity of metabolites were very heterogeneous, ranging from 31 to >10 000 features. Four studies used untargeted profiling. Different types of metabolites were associated with CVD risk: acylcarnitines, dicarboxylacylcarnitines, and several amino acids and lipid classes. Only tiny improvements in CVD prediction beyond traditional risk factors were observed using these metabolites (C index improvement ranged from 0.006 to 0.05).ConclusionsThere are a limited number of longitudinal studies assessing associations between comprehensive metabolomic profiles and CVD risk. Quantitatively synthesizing the literature is challenging because of the widely varying analytical tools and the diversity of methodological and statistical approaches. Although some results are promising, more research is needed, notably standardization of metabolomic techniques and statistical approaches. Replication and combinations of novel and holistic methodological approaches would move the field toward the realization of its promise.

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“…Besides regulating the metabolism of gluco‐lipids and adipogenisis, PPARγ has an anti‐inflammatory effect . A large number of studies have reported that PPARγ plays above‐mentioned roles mainly via two mechanisms . One is the trans‐activation of PPARγ‐dependent insulin pathway, and the other is the trans‐repression of PPARγ‐dependent NFκB pathway.…”

Section: Discussionmentioning

confidence: 99%

Trans‐repression of NFκB pathway mediated by PPARγ improves vascular endothelium insulin resistance

Kong

Gao

Lan

et al. 2018

J Cellular Molecular Medi

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Previous study has shown that thiazolidinediones (TZDs) improved endothelium insulin resistance (IR) induced by high glucose concentration (HG)/hyperglycaemia through a PPARγ‐dependent‐NFκB trans‐repression mechanism. However, it is unclear, whether changes in PPARγ expression affect the endothelium IR and what the underlying mechanism is. In the present study, we aimed to address this issue. HG‐treated human umbilical vascular endothelial cells (HUVEC) were transfected by either PPARγ‐overexpressing (Ad‐PPARγ) or PPARγ‐shRNA‐containing (Ad‐PPARγ‐shRNA) adenoviral vectors. Likewise, the rats fed by high‐fat diet (HFD) were infected by intravenous administration of Ad‐PPARγ or Ad‐PPARγ‐shRNA. The levels of nitric oxide (NO), endothelin‐1 (ET‐1) and cytokines (TNFα, IL‐6, sICAM‐1 and sVCAM‐1) and the expression levels of PPARγ, eNOS, AKT, p‐AKT, IKKα/β and p‐IKKα/β and IκBα were examined; and the interaction between PPARγ and NFκB‐P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPARγ notably increased the levels of NO, eNOS, p‐AKT and IκBα as well as the interaction of PPARγ and NFκB‐P65, and decreased the levels of ET‐1, p‐IKKα/β, TNFα, IL‐6, sICAM‐1 and sVCAM‐1. In contrast, down‐expression of PPARγ displayed the opposite effects. The results demonstrate that the overexpression of PPARγ improves while the down‐expression worsens the endothelium IR via a PPARγ‐mediated NFκB trans‐repression dependent manner. The findings suggest PPARγ is a potential therapeutic target for diabetic vascular complications.

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Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance

Cited by 36 publications

References 36 publications

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

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

Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review

Trans‐repression of NFκB pathway mediated by PPARγ improves vascular endothelium insulin resistance

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