Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation
Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation
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DOI：
10.1172/jci4532
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发表时间：
1998-11-01
影响因子：
15.9
通讯作者：
Kozak, LP
中科院分区：
文献类型：
--
作者：
Guerra, C;Koza, RA;Kozak, LP
当放在寒冷的地方（4 ℃）时，与对照品系C57 BL/6 J相比，两种性别的BALB/cByJ小鼠迅速失去体温。这种对冷的敏感性类似于先前描述的由于棕色脂肪细胞特异性线粒体解偶联蛋白基因Ucp 1的靶向失活而导致非颤抖性产热缺陷的小鼠，该性状的遗传作图将该基因置于染色体5上靠近Acads的位置，Acads是一种编码短链酰基CoA脱氢酶的基因，其在BALB/cByJ小鼠中突变。对该区域中候选基因的分析表明，仅Acads的表达存在缺陷，脂肪酸氧化对产热的重要性的确认来自我们的发现，即携带长链酰基CoA脱氢酶基因（Acadl）的靶向失活的小鼠也对冷敏感，这两种突变减弱了棕色脂肪细胞中通常对肾上腺素能信号传导有反应的基因的诱导。这些结果表明，脂肪酸作为基因表达调节因子的作用在突变小鼠中受到了干扰。从临床的角度来看，重要的是要确定是否在产热缺陷可能是一种表型在人类新生儿遗传缺陷的脂肪酸B-氧化。
When placed in the cold (4 degrees C), 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 B-oxidation.