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

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• 作者：Edgars Liepinsh^a ; ^{ledgars@biomed.lu.lv" class="auth_mail" title="E-mail the corresponding author} ; Marina Makrecka-Kuka^a ; ^b ; Elina Makarova^a ; Kristine Volska^a ; Baiba Svalbe^a ; Eduards Sevostjanovs^a ; Solveiga Grinberga^a ; Janis Kuka^a ; Maija Dambrova^a ; ^b
• 关键词：ACOX1 ; acyl-CoA oxidase 1 ; ACSL ; long-chain fatty acid CoA synthetase ; CPT1 ; carnitine palmitoyltransferase-1 ; FABP3 ; fatty acid binding protein 3 ; HFD ; high fat diet ; LCFA ; long-chain fatty acids ; Methyl-GBB ; 4-[ethyl(dimethyl)ammonio]butanoate ; OCTN2 ; organic cation transporter 2 ; PGC1α ; peroxisome proliferator-activated receptor-γ coactivator 1α ; PPARα ; peroxisome proliferator-activated receptor alpha
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：113
• 期：part_PB
• 页码：788-795
• 全文大小：1552 K

文摘

The important pathological consequences of insulin resistance arise from the detrimental effects of accumulated long-chain fatty acids and their respective acylcarnitines. The aim of this study was to test whether exercise combined with decreasing the content of long-chain acylcarnitines represents an effective strategy to improve insulin sensitivity in diabetes.

We used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB), treatment and exercise to decrease acylcarnitine contents in the plasma and muscles in the insulin resistance models of high fat diet (HFD) fed C57BL/6 mice and db/db mice.

The methyl-GBB treatment induced a substantial decrease in all acylcarnitine concentrations in both fed and fasted states as well as when it was combined with exercise. In the HFD fed mice methyl-GBB treatment improved both glucose and insulin tolerance. Methyl-GBB administration, exercise and the combination of both improved insulin sensitivity and reduced blood glucose levels in db/db mice. Methyl-GBB administration and the combination of the drug and exercise activated the PPARα/PGC1α signaling pathway and stimulated the corresponding target gene expression. Insulin insensitivity in db/db mice was not induced by significantly increased fatty acid metabolism, while increased insulin sensitivity by both treatments was not related to decreased fatty acid metabolism in muscles.

The pharmacologically reduced long-chain acylcarnitine content represents an effective strategy to improve insulin sensitivity. The methyl-GBB treatment and lifestyle changes via increased physical activity for one hour a day have additive insulin sensitizing effects in db/db mice.