Nordström Elisabet Arvidsson, Rydén Mikael, Backlund Emma C, Dahlman Ingrid, Kaaman Maria, Blomqvist Lennart, Cannon Barbara, Nedergaard Jan, Arner Peter
Professor, Karolinska Institutet, Karolinska University Hospital Huddinge, M63 SE-141 86 Stockholm, Sweden.
Diabetes. 2005 Jun;54(6):1726-34. doi: 10.2337/diabetes.54.6.1726.
Elevated circulating fatty acid concentration is a hallmark of insulin resistance and is at least in part attributed to the action of adipose tissue-derived tumor necrosis factor-alpha (TNF-alpha) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDEA is unknown, but CIDEA-null mice are resistant to obesity and diabetes. We investigated CIDEA in adipose tissue of obese and lean humans and mice. The mRNA was expressed in white human fat cells and in brown mouse adipocytes. The adipose mRNA expression of CIDEA in mice was not influenced by obesity. However, CIDEA expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDEA expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDEA by RNA interference stimulated lipolysis and increased TNF-alpha secretion by a posttranscriptional effect. Conversely, TNF-alpha treatment decreased adipocyte CIDEA expression via the mitogen-activated protein kinase c-Jun NH(2)-terminal kinase. We propose an important and human-specific role for CIDEA in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDEA and TNF-alpha.
循环脂肪酸浓度升高是胰岛素抵抗的一个标志，并且至少部分归因于脂肪组织衍生的肿瘤坏死因子-α（TNF-α）对脂肪分解的作用。细胞死亡诱导DNA片段化因子-α（DFFA）样效应因子A（CIDEA）属于促凋亡蛋白家族，在人类和小鼠中有五个已知成员。CIDEA的作用尚不清楚，但缺乏CIDEA的小鼠对肥胖和糖尿病具有抗性。我们研究了肥胖和瘦的人类及小鼠脂肪组织中的CIDEA。该mRNA在人类白色脂肪细胞和小鼠棕色脂肪细胞中表达。小鼠中CIDEA的脂肪mRNA表达不受肥胖影响。然而，肥胖人类中CIDEA表达降低了两倍，体重减轻后恢复正常。低水平的脂肪CIDEA表达与代谢综合征的几个特征相关。通过RNA干扰使人类脂肪细胞中的CIDEA缺失，通过转录后效应刺激了脂肪分解并增加了TNF-α分泌。相反，TNF-α处理通过丝裂原活化蛋白激酶c-Jun NH(2)-末端激酶降低了脂肪细胞CIDEA表达。我们提出CIDEA在脂肪分解调节和肥胖的代谢并发症中具有重要的、人类特异性的作用，这至少部分是由CIDEA和TNF-α之间的相互作用介导的。
