Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4.
Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4.
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DOI：
10.1016/j.cmet.2014.03.024
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发表时间：
2014-06-03
期刊：
影响因子：
29
通讯作者：
Montminy M
中科院分区：
文献类型：
--
作者：
Luan B;Goodarzi MO;Phillips NG;Guo X;Chen YD;Yao J;Allison M;Rotter JI;Shaw R;Montminy M
肥胖通过炎症变化促进系统性胰岛素抵抗，炎症变化导致细胞因子从活化的巨噬细胞中释放。尽管其机制尚不清楚，但已发现第二信使cAMP响应于多种激素信号而减弱巨噬细胞活性。我们发现，在急性营养过剩的情况下，瘦素触发cAMP信号的儿茶酚胺依赖性增加，通过激活组蛋白去乙酰化酶HDAC 4减少炎症基因的表达。cAMP通过PKA依赖性抑制盐诱导型激酶（SIKs）刺激HDAC 4活性，否则盐诱导型激酶（SIKs）将HDAC 4磷酸化并螯合在细胞质中。在其去磷酸化后，HDAC 4穿梭到细胞核，在那里它抑制NFkB对促炎基因的活性。由于HDAC 4基因的变体与人类肥胖相关，我们的结果表明cAMP-HDAC 4途径通过其对先天免疫系统的影响在维持胰岛素敏感性和能量平衡方面发挥重要作用。
Obesity promotes systemic insulin resistance through inflammatory changes that lead to the release of cytokines from activated macrophages. Although the mechanism is unclear, the second messenger cAMP has been found to attenuate macrophage activity in response to a variety of hormonal signals. We show that, in the setting of acute over-nutrition, leptin triggers catecholamine-dependent increases in cAMP signaling that reduce inflammatory gene expression via the activation of the histone deacetylase HDAC4. cAMP stimulates HDAC4 activity through the PKA-dependent inhibition of the salt inducible kinases (SIKs), which otherwise phosphorylate and sequester HDAC4 in the cytoplasm. Following its dephosphorylation, HDAC4 shuttles to the nucleus where it inhibits NFkB activity over pro-inflammatory genes. As variants in the HDAC4 gene are associated with obesity in humans, our results indicate that the cAMP-HDAC4 pathway functions importantly in maintaining insulin sensitivity and energy balance via its effects on the innate immune system.
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影响因子：
64.8
作者：
Nguyen, Khoa D.;Qiu, Yifu;Cui, Xiaojin;Goh, Y. P. Sharon;Mwangi, Julia;David, Tovo;Mukundan, Lata;Brombacher, Frank;Locksley, Richard M.;Chawla, Ajay
通讯作者：
Chawla, Ajay
影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
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：
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影响因子：
82.9
作者：
Altarejos, Judith Y.;Goebel, Naomi;Conkright, Michael D.;Inotiel, Hiroshi;Xie, Jianxin;Arias, Carlos M.;Sawchenko, Paul E.;Montminy, Marc
通讯作者：
Montminy, Marc