Activation of the adipocyte CREB/CRTC pathway in obesity.
Activation of the adipocyte CREB/CRTC pathway in obesity.
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DOI：
10.1038/s42003-021-02735-5
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发表时间：
2021-10-22
影响因子：
5.9
通讯作者：
Montminy M
中科院分区：
文献类型：
--
作者：
Yoon YS;Liu W;Van de Velde S;Matsumura S;Wiater E;Huang L;Montminy M
肥胖是II型糖尿病发展的主要危险因素。脂肪组织质量的增加通过从脂肪细胞和巨噬细胞释放促炎细胞因子触发胰岛素抵抗。CREB和CRTC共激活因子已被发现促进肥胖患者的胰岛素抵抗，尽管其机制尚不清楚。在这里，我们表明，高脂饮食喂养激活CREB/CRTC途径在脂肪细胞中通过减少SIK 2的表达，丝氨酸/苏氨酸激酶磷酸化和抑制CRTC。SIK 2水平受成脂因子C/EBPα调节，其表达在肥胖症中减少。暴露于PPARγ激动剂可挽救C/EBPα表达并恢复SIK 2水平。CRTC 2/3通过诱导趋化因子CXCL 1/2促进胰岛素抵抗。脂肪细胞中CRTC 2/3的敲除降低了CXCL 1/2的表达并改善了胰岛素敏感性。由于CXCL 1/2的给药逆转了CRTC 2/3耗竭的有益作用，我们的研究结果证明了CREB/CRTC通路在调节脂肪组织功能中的重要性。Yoon等人表明，小鼠中的高脂肪饮食通过降低盐诱导激酶2（SIK 2）的表达来激活脂肪细胞中的CREB/CRTC途径，所述盐诱导激酶2是一种丝氨酸/苏氨酸激酶，否则其磷酸化并螯合细胞质中的CREB共激活因子。他们的数据表明CREB/CRTC通路在介导肥胖对脂肪细胞功能的影响中的重要性。
Obesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function. Yoon et al show that a high fat diet in mice activates the CREB/CRTC pathway in adipocytes by decreasing the expression of Salt Inducible Kinase 2 (SIK2), a Ser/Thr kinase that otherwise phosphorylates and sequesters CREB coactivators in the cytoplasm. Their data demonstrates the importance of the CREB/CRTC pathway in mediating effects of obesity on adipocyte function.
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影响因子：
39.3
作者：
Liu T;Zhang L;Joo D;Sun SC
通讯作者：
Sun SC
影响因子：
7.7
作者：
Mantovani G;Bondioni S;Alberti L;Gilardini L;Invitti C;Corbetta S;Zappa MA;Ferrero S;Lania AG;Bosari S;Beck-Peccoz P;Spada A
通讯作者：
Spada A
DOI：
10.1016/j.bbadis.2013.05.017
发表时间：
2014-03
影响因子：
6.2
作者：
Lee, Byung-Cheol;Lee, Jongsoon
通讯作者：
Lee, Jongsoon
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
29
作者：
Luan B;Goodarzi MO;Phillips NG;Guo X;Chen YD;Yao J;Allison M;Rotter JI;Shaw R;Montminy M
通讯作者：
Montminy M