Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation.
When placed in the cold (4 degreesC), BALB/cByJ mice of both genders rapidly lose body temperature as compared with the control strain, C57BL/6J. This sensitivity to cold resembles that previously described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1. Genetic mapping of the trait placed the gene on chromosome 5 near Acads, a gene encoding the short chain acyl CoA dehydrogenase, which is mutated in BALB/cByJ mice. The analysis of candidate genes in the region indicated a defect only in the expression of Acads. Confirmation of the importance of fatty acid oxidation to thermogenesis came from our finding that mice carrying the targeted inactivation of the long chain acyl CoA dehydrogenase gene (Acadl) are also sensitive to the cold. Both of these mutations attenuate the induction of genes normally responsive to adrenergic signaling in brown adipocytes. These results suggest that the action of fatty acids as regulators of gene expression has been perturbed in the mutant mice. From a clinical perspective, it is important to determine whether defects in thermogenesis may be a phenotype in human neonates with inherited deficiencies in fatty acid beta-oxidation.
Guerra
C
C
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Koza
R A
RA
Walsh
K
K
Kurtz
D M
DM
Wood
P A
PA
Kozak
L P
LP
D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001833:Body Temperature Regulation / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003080:Cold Temperature; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D007473:Ion Channels; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D005227:Fatty Acids; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain