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Article: Inhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance

TitleInhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance
Authors
Issue Date2012
Citation
American Journal of Physiology - Endocrinology and Metabolism, 2012, v. 303 n. 12, p. E1459-E1468 How to Cite?
AbstractWe previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM- 301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications. © 2012 the American Physiological Society.
Persistent Identifierhttp://hdl.handle.net/10722/195870
ISSN
2015 Impact Factor: 3.825
2015 SCImago Journal Rankings: 2.465
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSamokhvalov, V-
dc.contributor.authorUssher, JR-
dc.contributor.authorFillmore, N-
dc.contributor.authorArmstrong, IKG-
dc.contributor.authorKeung, W-
dc.contributor.authorMoroz, D-
dc.contributor.authorLopaschuk, DG-
dc.contributor.authorSeubert, J-
dc.contributor.authorLopaschuk, GD-
dc.date.accessioned2014-03-19T01:46:11Z-
dc.date.available2014-03-19T01:46:11Z-
dc.date.issued2012-
dc.identifier.citationAmerican Journal of Physiology - Endocrinology and Metabolism, 2012, v. 303 n. 12, p. E1459-E1468-
dc.identifier.issn0193-1849-
dc.identifier.urihttp://hdl.handle.net/10722/195870-
dc.description.abstractWe previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM- 301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications. © 2012 the American Physiological Society.-
dc.languageeng-
dc.relation.ispartofAmerican Journal of Physiology - Endocrinology and Metabolism-
dc.titleInhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1152/ajpendo.00018.2012-
dc.identifier.pmid23074239-
dc.identifier.scopuseid_2-s2.0-84871313172-
dc.identifier.hkuros239602-
dc.identifier.volume303-
dc.identifier.issue12-
dc.identifier.spageE1459-
dc.identifier.epageE1468-
dc.identifier.isiWOS:000312586100007-

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