Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance
Deficiency in the short-chain acyl-CoA dehydrogenase protects mice against diet-induced obesity and insulin resistance
复制标题
短链酰基辅酶A脱氢酶缺乏可保护小鼠免受饮食引起的肥胖和胰岛素抵抗
DOI：
10.1096/fj.201901474rr
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Su, Zhiguang
中科院分区：
文献类型：
--
作者：
Chen, Yulong;Chen, Jinglu;Su, Zhiguang
酰辅酶A脱氢酶(CADS)参与线粒体脂肪酸氧化；脂肪酸氧化异常与肥胖及相关代谢紊乱有关。我们破译了短链CAD(SCAD)对肥胖和胰岛素抵抗的影响。来源于BALB/c品系的BALB/CBY品系小鼠由于酰基辅酶A脱氢酶(Acads)基因的自发缺失而导致SCAD活性缺陷。比较了BALB/c和BALB/CBY小鼠在高脂饮食(HFDs)下的肥胖、脂肪生成和胰岛素敏感性。利用基因芯片进行全肝转录组图谱实验，以评估SCAD缺陷保护胰岛素抵抗的机制。与对照小鼠相比，ACADS基因缺陷小鼠对高脂饮食诱导的肥胖和胰岛素抵抗具有显著的抵抗力。肥胖的减轻是由于肝脏中AMPK的激活导致甘油三酯含量降低，从而减少了肝脏丙二酰辅酶A的含量，导致肝脏新生脂肪生成减少。胰岛素敏感性的改善与肝脏和骨骼肌中二酰甘油含量的减少、PKC-epsilon活性的降低和蛋白激酶B(AKT)的活性增加相关联。此外，ACADS缺陷小鼠的内质伴侣78-kDa葡萄糖调节蛋白的表达显著增加，这进一步与原代肝细胞中AKT的激活有关。因此，调控SCAD的表达可能是管理和预防肥胖和相关代谢性疾病(如糖尿病)的一种新的治疗方法。
Acyl-CoA dehydrogenases (CADs) participate in mitochondrial fatty acid oxidation; abnormal fatty acid oxidation is associated with obesity and related metabolic disorders. We decipher the impact of short-chain CAD (SCAD) on adiposity and insulin resistance. BALB/cBy strain mice derived from BALB/c strain are deficient in SCAD activity because of a spontaneous deletion in the acyl-CoA dehydrogenases (Acads) gene. Adiposity, lipogenesis, and insulin sensitivity were compared in BALB/c and BALB/cBy mice subjected to high-fat diets (HFDs). A whole hepatic transcriptome profiling experiment with microarrays was performed to evaluate the mechanisms by which SCAD deficiency protects against insulin resistance. Acads-deficient mice were significantly resistant to HFD-induced obesity and insulin resistance as compared with control mice. Reduced obesity results from decreased triglyceride content due to activation of AMPK in liver that would reduce hepatic content of malonyl-CoA, resulting in decreased hepatic de novo lipogenesis. Improved insulin sensitivity was associated with reduced diacylglycerol content commensurate with reduced PKC-epsilon activity and increased protein kinase B (AKT) activation in liver and skeletal muscle. Additionally, Acads-deficient mice displayed significantly higher expression of the endoplasmic chaperone 78-kDa glucose-regulated protein, which was further associated with the AKT activation in the primary hepatocytes. Modulation of SCAD expression may therefore be a novel therapeutic approach to manage and prevent obesity and related metabolic diseases, such as diabetes.