CRTC3 links catecholamine signalling to energy balance.
CRTC3 links catecholamine signalling to energy balance.
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作者：
在瘦肉条件下，脂肪来源的激素瘦素部分通过中枢神经系统介导的交感神经流出增加来维持能量平衡，从而增强脂肪燃烧。触发脂肪细胞中的β肾上腺素能受体通过camp依赖性的脂肪分解和脂肪酸氧化增加来刺激能量消耗。虽然潜在的机制尚不清楚，但脂肪细胞中的儿茶酚胺信号被认为在肥胖中被破坏，这可能导致肝脏中脂质的异位积累和胰岛素抵抗的发展。在这里，我们表明cAMP响应CREB共激活因子CRTC3通过减弱脂肪中的β肾上腺素能受体信号传导促进肥胖；敲除CRTC3基因的小鼠能量消耗增加，对饮食引起的肥胖具有抗性，并且在高脂肪饮食喂养条件下免受肝脏脂肪变性的影响。CRTC3在儿茶酚胺信号的作用下被激活，通过上调代谢综合征易感基因RGS2的表达来降低腺苷环化酶的活性，我们在这里发现RGS2也是CREB和CRTC3的直接靶点。RGS2在CRTC3−/−小鼠脂肪细胞中的表达下调，导致胰岛素和儿茶酚胺信号的增加，从而增强葡萄糖和脂肪酸氧化。由于在两个不同的墨西哥裔美国人群中，一种常见的人类CRTC3变体（Ser72Asn）的转录活性增加，与几种肥胖人体测量指标相关，我们的研究结果表明，脂肪细胞CRTC3可能在该人群的肥胖发展中发挥作用。
Under lean conditions, the adipose-derived hormone leptin maintains energy balance in part through CNS-mediated increases in sympathetic outflow that enhance fat burning. Triggering of beta adrenergic receptors in adipocytes stimulates energy expenditure via cAMP-dependent increases in lipolysis and fatty acid oxidation. Although the underlying mechanism is unclear, catecholamine signaling in fat cells is thought to be disrupted in obesity, where it may contribute to the ectopic accumulation of lipid in liver and to the development of insulin resistance. Here we show that the cAMP responsive CREB coactivator CRTC3 promotes obesity by attenuating beta adrenergic receptor signaling in adipose; mice with a knockout of the CRTC3 gene have increased energy expenditure, are resistant to diet induced obesity, and are protected from the development of hepatic steatosis under high fat diet feeding conditions. CRTC3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of RGS2, a metabolic syndrome susceptibility gene, which we show here is also a direct target of CREB and CRTC3. RGS2 expression was down-regulated in adipocytes from CRTC3−/− mice, leading to increases in insulin and catecholamine signaling that enhanced glucose and fatty acid oxidation. As a common human CRTC3 variant (Ser72Asn), with increased transcriptional activity, is associated with several anthropometric indices of adiposity in two distinct Mexican-American cohorts, our results suggest that adipocyte CRTC3 may play a role in the development of obesity in this population.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
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
影响因子：
4.5
作者：
Heard-Costa NL;Zillikens MC;Monda KL;Johansson A;Harris TB;Fu M;Haritunians T;Feitosa MF;Aspelund T;Eiriksdottir G;Garcia M;Launer LJ;Smith AV;Mitchell BD;McArdle PF;Shuldiner AR;Bielinski SJ;Boerwinkle E;Brancati F;Demerath EW;Pankow JS;Arnold AM;Chen YD;Glazer NL;McKnight B;Psaty BM;Rotter JI;Amin N;Campbell H;Gyllensten U;Pattaro C;Pramstaller PP;Rudan I;Struchalin M;Vitart V;Gao X;Kraja A;Province MA;Zhang Q;Atwood LD;Dupuis J;Hirschhorn JN;Jaquish CE;O'Donnell CJ;Vasan RS;White CC;Aulchenko YS;Estrada K;Hofman A;Rivadeneira F;Uitterlinden AG;Witteman JC;Oostra BA;Kaplan RC;Gudnason V;O'Connell JR;Borecki IB;van Duijn CM;Cupples LA;Fox CS;North KE
通讯作者：
North KE
DOI：
10.1073/pnas.1932773100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Iourgenko, V;Zhang, WJ;Labow, MA
通讯作者：
Labow, MA
影响因子：
5.4
作者：
Katoh, Yoshiko;Takemori, Hiroshi;Okamoto, Mitsuhiro
通讯作者：
Okamoto, Mitsuhiro