title: Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models.
abstract: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (FAO). Patients with VLCAD deficiency may present with hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy. Although several mouse models have been developed to aid in the study of the pathogenesis of long-chain FAO defects, the muscular phenotype is underexposed. To address the muscular phenotype, we used a newly developed mouse model on a mixed genetic background with a more severe defect in FAO (LCAD(-/-); VLCAD(+/-)) in addition to a validated mouse model (LCAD(-/-); VLCAD(+/+)) and compared them with wild-type (WT) mice. We found that both mouse models show a 20% reduction in energy expenditure (EE) and a 3-fold decrease in locomotor activity in the unfed state. In addition, we found a 1.7°C drop in body temperature in unfed LCAD(-/-); VLCAD(+/+) mice compared with WT body temperature. We conclude that food withdrawal-induced inactivity, hypothermia, and reduction in EE are novel phenotypes associated with FAO deficiency in mice. Unexpectedly, inactivity was not explained by rhabdomyolysis, but rather reflected the overall reduced capacity of these mice to generate heat. We suggest that mice are partly protected against the negative consequence of an FAO defect.-Diekman, E. F., van Weeghel, M., Wanders, R. J. A., Visser, G., Houten, S. M. Food withdrawal lowers energy expenditure and induces inactivity in long-chain fatty acid oxidation-deficient mouse models.
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center (UMC) Utrecht, the Netherlands; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and.
authors.forename: Eugene F
authors.initials: EF
authors.lastname: Diekman
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and.
authors.forename: Michel
authors.initials: M
authors.lastname: van Weeghel
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center (UMC) Utrecht, the Netherlands;
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, and Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA sander.houten@mssm.edu.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D000080984:Congenital Bone Marrow Failure Syndromes; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000503:physiopathology*; D009043:Motor Activity / Q000502:physiology; D009135:Muscular Diseases / Q000378:metabolism / Q000503:physiopathology*; D010084:Oxidation-Reduction; D010641:Phenotype; D012206:Rhabdomyolysis / Q000378:metabolism / Q000503:physiopathology
chemical_list: D005227:Fatty Acids; D044942:Acyl-CoA Dehydrogenase, Long-Chain
keywords: creatine kinase; myopathy; rhabdomyolysis; thermogenesis