The Creb1 coactivator Crtc1 is required for energy balance and fertility.
The Creb1 coactivator Crtc1 is required for energy balance and fertility.
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DOI：
10.1038/nm.1866
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发表时间：
2008-10
期刊：
影响因子：
82.9
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
--
作者：
Altarejos, Judith Y.;Goebel, Naomi;Conkright, Michael D.;Inotiel, Hiroshi;Xie, Jianxin;Arias, Carlos M.;Sawchenko, Paul E.;Montminy, Marc
肥胖是胰岛素抵抗和2型糖尿病的主要风险因素，脂肪细胞衍生的马酮瘦素通过对下丘脑瘦素受体（LRB）的作用来维持能量平衡LRB-STAT3信号的破坏促进了小鼠的肥胖症，LRB功能的其他神经内分泌特征，例如生育能力正常，指出对在此环境中，我们表明cAMP和钙响应的CREB共激活器TORC1是能量平衡和繁殖所必需的。它们具有异常的子宫形态，以及低循环的叶酸叶型马酮。反过来的活性torc1反过来刺激了CART和KISS1基因的表达，这些基因编码下丘脑神经肽，介导瘦素对饱腹感和生育能力分别介导了培养的下表达。 torc1，by RNAi在体内介导的敲低或靶向基因破坏，降低了cAMP和钙激活剂对CART上的Torc1转录活性的潜在影响，而在过表达LRB的细胞中，cAMP和cAMP激活者的转录活性降低了。负CREB多肽A-creb。 Vivo，我们的结果表明，CREB：TORC1途径介导了马酮和养分信号对能量平衡和生育能力的中心作用。
Obesity is a major risk factor in the development of insulin resistance and Type 2 diabetes. Under lean conditions, the adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (LRbs) that trigger activation of the JAK2/STAT3 pathway. Although disruption of LRb-STAT3 signaling promotes obesity in mice, other neuroendocrine features of LRb function such as fertility appear normal, pointing to a requirement for additional regulators in this setting. Here we show that the cAMP and calcium-responsive CREB coactivator TORC1 is required for energy balance and reproduction; TORC1 −/− mice are hyperphagic, obese, and infertile. Indeed, TORC1−/− females are anovulatory, and they have abnormal uterine morphology along with low circulating concentrations of pituitary luteinizing hormone. Hypothalamic TORC1 was highly phosphorylated and inactive in leptin deficient ob/ob mice; and administration of leptin increased amounts of dephosphorylated, nuclear TORC1. Dephosphorylated, active TORC1, in turn, stimulated the expression of CART and KISS1 genes, which encode hypothalamic neuropeptides that mediate leptin effects on satiety and fertility, respectively. TORC1 over-expression in cultured hypothalamic cells increased CART and KISS1 gene expression, while depletion of TORC1, by RNAi mediated knockdown in vitro or by targeted gene disruption in vivo, decreased it. Leptin potentiated effects of cAMP and calcium activators on TORC1 transcriptional activity over the CART and KISS1 promoters in cells over-expressing LRb; these effects were disrupted by expression of the dominant negative CREB polypeptide A-CREB. As leptin administration also increased recruitment of hypothalamic TORC1 to CART and KISS1 promoters in vivo, our results indicate that the CREB:TORC1 pathway mediates central effects of hormone and nutrient signals on energy balance and fertility.
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