Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea.
PLoS Genet. 2013;9(3):e1003356. doi: 10.1371/journal.pgen.1003356. Epub 2013 Mar 14.
Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS-deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA-encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance.
线粒体氧化磷酸化（OXPHOS）受损被认为是导致胰岛素抵抗的一种发病机制。然而，在系统性胰岛素抵抗发展过程中，导致 OXPHOS 功能障碍的起始器官尚未确定。为了确定脂肪组织 OXPHOS 缺陷是否在系统性胰岛素抵抗中起病因作用，研究了 OXPHOS 缺陷脂肪组织小鼠的代谢表型。Crif1 是一种在线粒体中产生 mtDNA 编码的 OXPHOS 亚基所必需的蛋白质；因此，Crif1 杂合不足的小鼠会导致体内 OXPHOS 能力出现轻微但特异性的衰竭。尽管脂肪组织特异性的 Crif1 杂合不足小鼠表现出正常的生长和发育，但它们仍会出现胰岛素抵抗。沉默的 Crif1 脂肪细胞表现出更高的趋化因子表达，其表达依赖于应激激酶和抗氧化剂。因此，对 Crif1 杂合不足小鼠的脂肪组织进行检查发现，MCP1 和 TNFα 的分泌增加，以及巨噬细胞的明显浸润。这些发现表明，脂肪组织的 OXPHOS 状态决定了其代谢和炎症反应，并可能导致全身炎症和胰岛素抵抗。
