Department of Experimental Diabetology and Pharmacology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
Endocrinology. 2011 Dec;152(12):4641-51. doi: 10.1210/en.2011-1547. Epub 2011 Oct 11.
Dysregulation of fatty acid oxidation plays a pivotal role in the pathophysiology of obesity and insulin resistance. Medium- and short-chain-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (SCHAD) (gene name, hadh) catalyze the third reaction of the mitochondrial β-oxidation cascade, the oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, for medium- and short-chain fatty acids. We identified hadh as a putative obesity gene by comparison of two genome-wide scans, a quantitative trait locus analysis previously performed in the polygenic obese New Zealand obese mouse and an earlier described small interfering RNA-mediated mutagenesis in Caenorhabditis elegans. In the present study, we show that mice lacking SCHAD (hadh(-/-)) displayed a lower body weight and a reduced fat mass in comparison with hadh(+/+) mice under high-fat diet conditions, presumably due to an impaired fuel efficiency, the loss of acylcarnitines via the urine, and increased body temperature. Food intake, total energy expenditure, and locomotor activity were not altered in knockout mice. Hadh(-/-) mice exhibited normal fat tolerance at 20 C. However, during cold exposure, knockout mice were unable to clear triglycerides from the plasma and to maintain their normal body temperature, indicating that SCHAD plays an important role in adaptive thermogenesis. Blood glucose concentrations in the fasted and postprandial state were significantly lower in hadh(-/-) mice, whereas insulin levels were elevated. Accordingly, insulin secretion in response to glucose and glucose plus palmitate was elevated in isolated islets of knockout mice. Therefore, our data indicate that SCHAD is involved in thermogenesis, in the maintenance of body weight, and in the regulation of nutrient-stimulated insulin secretion.
脂肪酸氧化失调在肥胖和胰岛素抵抗的病理生理学中起着关键作用。中链和短链 3-羟酰基辅酶 A（CoA）脱氢酶（SCHAD）（基因名称，hadh）催化线粒体β-氧化级联的第三个反应，即 3-羟酰基辅酶 A 氧化为 3-酮酰基辅酶 A，用于中链和短链脂肪酸。我们通过比较两个全基因组扫描、先前在多基因肥胖新西兰肥胖小鼠中进行的定量性状位点分析以及先前在秀丽隐杆线虫中描述的小干扰 RNA 介导的诱变，将 hadh 鉴定为一个假定的肥胖基因。在本研究中，我们发现与 hadh(+/+) 小鼠相比，缺乏 SCHAD（hadh(-/-)）的小鼠在高脂肪饮食条件下体重较低，脂肪量减少，这可能是由于燃料效率受损、通过尿液丧失酰基辅酶 A 以及体温升高所致。敲除小鼠的食物摄入量、总能量消耗和运动活性没有改变。在 20°C 时，hadh(-/-) 小鼠的脂肪耐受性正常。然而，在寒冷暴露期间，敲除小鼠无法从血浆中清除甘油三酯并维持其正常体温，表明 SCHAD 在适应性产热中发挥重要作用。禁食和餐后状态下 hadh(-/-) 小鼠的血糖浓度显著降低，而胰岛素水平升高。因此，与野生型相比，敲除小鼠胰岛对葡萄糖和葡萄糖加棕榈酸的胰岛素分泌增加。因此，我们的数据表明 SCHAD 参与产热、体重维持和营养刺激的胰岛素分泌的调节。
