Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice
Recent reports suggest that short‐term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and t...
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| Published in | Diabetes, obesity & metabolism Vol. 16; no. 8; pp. 757 - 760 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford, UK
Blackwell Publishing Ltd
01.08.2014
Wiley Subscription Services, Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1462-8902 1463-1326 1463-1326 |
| DOI | 10.1111/dom.12248 |
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| Abstract | Recent reports suggest that short‐term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart‐ and skeletal muscle‐specific deletion of the Cpt1b, Cpt1bHM−/−. These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1bHM−/− mice. The hearts of Cpt1bHM−/− mice were four times the size of controls. Cpt1bHM−/− mice were also subject to stress‐induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. |
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| AbstractList | Recent reports suggest that short-term pharmacological Cpt1 inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. While this appears promising for the treatment of diabetes these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart and skeletal muscle specific deletion of the Cpt1b, Cpt1b
HM−/−
. These mice seem to develop normally with similar bodyweights as control mice. However, by 15 weeks of age the Cpt1b
HM−/−
mice begin to die. The hearts of Cpt1b
HM−/−
mice were 4-times the size of controls. Cpt1b
HM−/−
mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1b(HM-/-). These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b(HM-/-) mice. The hearts of Cpt1b(HM-/-) mice were four times the size of controls. Cpt1b(HM-/-) mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable.Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1b(HM-/-). These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b(HM-/-) mice. The hearts of Cpt1b(HM-/-) mice were four times the size of controls. Cpt1b(HM-/-) mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. Recent reports suggest that short‐term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart‐ and skeletal muscle‐specific deletion of the Cpt1b, Cpt1b HM −/− . These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b HM −/− mice. The hearts of Cpt1b HM −/− mice were four times the size of controls. Cpt1b HM −/− mice were also subject to stress‐induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. Recent reports suggest that short‐term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart‐ and skeletal muscle‐specific deletion of the Cpt1b, Cpt1bHM−/−. These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1bHM−/− mice. The hearts of Cpt1bHM−/− mice were four times the size of controls. Cpt1bHM−/− mice were also subject to stress‐induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1b(HM-/-). These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b(HM-/-) mice. The hearts of Cpt1b(HM-/-) mice were four times the size of controls. Cpt1b(HM-/-) mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1bHM-/-. These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15weeks of age in the Cpt1bHM-/- mice. The hearts of Cpt1bHM-/- mice were four times the size of controls. Cpt1bHM-/- mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable. [PUBLICATION ABSTRACT] |
| Author | Wicks, S. E. Vandanmagsar, B. Mynatt, R. L. Zhang, J. Haynie, K. R. |
| AuthorAffiliation | 1 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA |
| AuthorAffiliation_xml | – name: 1 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA |
| Author_xml | – sequence: 1 givenname: K. R. surname: Haynie fullname: Haynie, K. R. organization: Pennington Biomedical Research Center, Louisiana State University System, LA, Baton Rouge, USA – sequence: 2 givenname: B. surname: Vandanmagsar fullname: Vandanmagsar, B. organization: Pennington Biomedical Research Center, Louisiana State University System, LA, Baton Rouge, USA – sequence: 3 givenname: S. E. surname: Wicks fullname: Wicks, S. E. organization: Pennington Biomedical Research Center, Louisiana State University System, LA, Baton Rouge, USA – sequence: 4 givenname: J. surname: Zhang fullname: Zhang, J. organization: Pennington Biomedical Research Center, Louisiana State University System, LA, Baton Rouge, USA – sequence: 5 givenname: R. L. surname: Mynatt fullname: Mynatt, R. L. email: randall.mynatt@pbrc.edu organization: Pennington Biomedical Research Center, Louisiana State University System, LA, Baton Rouge, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24330405$$D View this record in MEDLINE/PubMed |
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| Keywords | carnitine palmitoyltransferase fatty acid oxidation cardiac hypertrophy observational study |
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| References | He L, Kim T, Long Q et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. Circulation 2012; 126: 1705-1716. Luiken JJ, Niessen HE, Coort SL et al. Etomoxir-induced partial carnitine palmitoyltransferase-I (CPT-I) inhibition in vivo does not alter cardiac long-chain fatty acid uptake and oxidation rates. Biochem J 2009; 419: 447-455. Cabrero A, Merlos M, Laguna JC, Carrera MV. Down-regulation of acyl-CoA oxidase gene expression and increased NF-κB activity in etomoxir-induced cardiac hypertrophy. J Lipid Res 2003; 44: 388-398. Timmers S, Nabben M, Bosma M et al. Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity. Proc Natl Acad Sci U S A 2012; 109: 11711-11716. Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001; 21: 89-104. Lopaschuk GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988; 63: 1036-1043. Holloway GP, Snook LA, Harris RJ, Glatz JF, Luiken JJ, Bonen A. In obese Zucker rats, lipids accumulate in the heart despite normal mitochondrial content, morphology and long-chain fatty acid oxidation. J Physiol 2011; 589: 169-180. Bonnet D, Martin D, Pascale De L et al. Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 1999; 100: 2248-2253. Bonnefont JP, Demaugre F, Prip-Buus C et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 1999; 68: 424-440. Keung W, Ussher JR, Jaswal JS, Raubenheimer M, Lam VH, Wagg CS, Lopaschuk GD. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice. Diabetes 2013; 62: 711-720. 2011; 589 1999; 68 2009; 419 1999; 100 1988; 63 2012; 126 2013; 62 2012; 109 2003; 44 2001; 21 e_1_2_7_6_1 e_1_2_7_11_1 e_1_2_7_5_1 e_1_2_7_10_1 e_1_2_7_4_1 e_1_2_7_3_1 e_1_2_7_9_1 e_1_2_7_8_1 e_1_2_7_7_1 e_1_2_7_2_1 22932257 - Circulation. 2012 Oct 2;126(14):1705-16 3197271 - Circ Res. 1988 Dec;63(6):1036-43 10577999 - Circulation. 1999 Nov 30;100(22):2248-53 11296700 - Semin Liver Dis. 2001;21(1):89-104 12576521 - J Lipid Res. 2003 Feb;44(2):388-98 21041527 - J Physiol. 2011 Jan 1;589(Pt 1):169-80 22753483 - Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11711-6 23139350 - Diabetes. 2013 Mar;62(3):711-20 10607472 - Mol Genet Metab. 1999 Dec;68(4):424-40 19138173 - Biochem J. 2009 Apr 15;419(2):447-55 |
| References_xml | – reference: Cabrero A, Merlos M, Laguna JC, Carrera MV. Down-regulation of acyl-CoA oxidase gene expression and increased NF-κB activity in etomoxir-induced cardiac hypertrophy. J Lipid Res 2003; 44: 388-398. – reference: Bonnefont JP, Demaugre F, Prip-Buus C et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 1999; 68: 424-440. – reference: Luiken JJ, Niessen HE, Coort SL et al. Etomoxir-induced partial carnitine palmitoyltransferase-I (CPT-I) inhibition in vivo does not alter cardiac long-chain fatty acid uptake and oxidation rates. Biochem J 2009; 419: 447-455. – reference: Bonnet D, Martin D, Pascale De L et al. Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 1999; 100: 2248-2253. – reference: He L, Kim T, Long Q et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. Circulation 2012; 126: 1705-1716. – reference: Timmers S, Nabben M, Bosma M et al. Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity. Proc Natl Acad Sci U S A 2012; 109: 11711-11716. – reference: Keung W, Ussher JR, Jaswal JS, Raubenheimer M, Lam VH, Wagg CS, Lopaschuk GD. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice. Diabetes 2013; 62: 711-720. – reference: Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001; 21: 89-104. – reference: Lopaschuk GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988; 63: 1036-1043. – reference: Holloway GP, Snook LA, Harris RJ, Glatz JF, Luiken JJ, Bonen A. In obese Zucker rats, lipids accumulate in the heart despite normal mitochondrial content, morphology and long-chain fatty acid oxidation. 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| Snippet | Recent reports suggest that short‐term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and... Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and... Recent reports suggest that short-term pharmacological Cpt1 inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. While this appears... |
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| SubjectTerms | Animals cardiac hypertrophy Cardiomegaly - chemically induced Cardiomegaly - enzymology Cardiomegaly - pathology Cardiomegaly - physiopathology Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - genetics Carnitine O-Palmitoyltransferase - metabolism Carnitine palmitoyltransferase Chimera Crosses, Genetic Diabetes mellitus Drugs, Investigational - adverse effects Enzyme Inhibitors - adverse effects fatty acid oxidation Female Glucose tolerance Heart - drug effects Heart - physiopathology Hypertrophy Hypoglycemic Agents - adverse effects Insulin Insulin Resistance Isoforms Male Mice, Inbred C57BL Mice, Knockout Mortality Muscle, Skeletal - drug effects Muscle, Skeletal - enzymology Muscle, Skeletal - physiopathology Musculoskeletal system Myocardium - enzymology Myocardium - pathology observational study Organ Size - drug effects Palmitoyltransferase Protein Isoforms - antagonists & inhibitors Protein Isoforms - genetics Protein Isoforms - metabolism Rodents Seizures Seizures - chemically induced Seizures - enzymology Seizures - pathology Seizures - physiopathology Skeletal muscle Survival Analysis |
| Title | Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice |
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