PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.
PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.
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发表时间：
2004
期刊：
影响因子：
82.9
通讯作者：
S. Koo;H. Satoh;S. Herzig;Chih‐Hao Lee;S. Hedrick;R. Kulkarni;R. Evans;J. Olefsky;M. Montminy-M.-Mo
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作者：
S. Koo;H. Satoh;S. Herzig;Chih‐Hao Lee;S. Hedrick;R. Kulkarni;R. Evans;J. Olefsky;M. Montminy-M.-Mo
胰岛素抵抗是2型糖尿病发展的主要标志，其特点是胰岛素抑制肝脏葡萄糖输出和促进肌肉葡萄糖摄取的能力受损。核激素受体共激活因子PGC-1（过氧化物酶体增殖物激活(PPAR)- γ共激活因子-1）与2型糖尿病的发病有关。在这种疾病的小鼠模型中，肝脏PGC-1表达升高，它分别通过与核激素受体HNF-4和ppar - α的关联促进糖异生和脂肪酸氧化的组成性激活。通过腺病毒向肝脏传递PGC-1 RNA干扰（RNAi）产生PGC-1缺陷小鼠，出现空腹低血糖。pgc -1缺陷小鼠的肝脏胰岛素敏感性增强，部分反映了哺乳动物tribbles同源物TRB-3的表达减少，TRB-3是丝氨酸-苏氨酸激酶Akt/PKB的禁食诱导抑制剂（参考文献6）。我们在这里表明，在肝脏中，TRB-3是ppar - α的靶标。敲低肝脏TRB-3表达可改善葡萄糖耐量，而肝脏TRB-3过表达可逆转pgc -1缺陷小鼠的胰岛素敏感表型。这些结果表明核激素受体和胰岛素信号通路之间存在联系，并提示TRB-3抑制剂在2型糖尿病治疗中的潜在作用。
Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-alpha. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.