title: Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice.
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, 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.
authors: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA.
authors: K R
authors: KR
authors: Haynie
authors: B
authors: B
authors: Vandanmagsar
authors: S E
authors: SE
authors: Wicks
authors: J
authors: J
authors: Zhang
authors: R L
authors: RL
authors: Mynatt
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002678:Chimera; D003433:Crosses, Genetic; D015507:Drugs, Investigational / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis
chemical_list: D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D020033:Protein Isoforms; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase
keywords: cardiac hypertrophy; carnitine palmitoyltransferase; fatty acid oxidation; observational study