PER2 controls lipid metabolism by direct regulation of PPARγ.
PER2 controls lipid metabolism by direct regulation of PPARγ.
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DOI：
10.1016/j.cmet.2010.10.005
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发表时间：
2010-11-03
期刊：
影响因子：
29
通讯作者：
Sassone-Corsi P
中科院分区：
文献类型：
--
作者：
Grimaldi B;Bellet MM;Katada S;Astarita G;Hirayama J;Amin RH;Granneman JG;Piomelli D;Leff T;Sassone-Corsi P
越来越多的证据凸显了生物钟和代谢途径之间有趣的相互作用。我们发现，PER2直接且特异性地抑制PPARγ，PPARγ是一种在脂肪生成、胰岛素敏感性和炎症反应中起关键作用的核受体。PER2缺陷型小鼠表现出脂质代谢改变，总甘油三酯和非酯化脂肪酸大幅减少。PER2通过阻止PPARγ募集到靶启动子从而抑制转录激活来发挥其抑制功能。全基因组微阵列分析表明，PER2决定了PPARγ转录活性的特异性。事实上，PER2的缺失导致培养的成纤维细胞的脂肪细胞分化增强。PER2作用于PPARγ的S112位点，该位点的突变与脂质代谢改变有关。脂质组学分析表明，PER2对于白色脂肪组织的正常脂质代谢是必需的。我们的研究结果支持这样一种情况：PER2作为PPARγ的天然调节剂来控制其促脂肪生成活性，从而揭示了药物和治疗干预的潜在途径。
Accumulating evidence highlights intriguing interplays between circadian and metabolic pathways. We show that PER2 directly and specifically represses PPARγ, a nuclear receptor critical in adipogenesis, insulin sensitivity and inflammatory response. PER2-deficient mice display altered lipid metabolism, with drastic reduction of total triacylglycerol and non-esterified fatty acids. PER2 exerts its inhibitory function by blocking PPARγ recruitment to target promoters and thereby transcriptional activation. Whole-genome microarray profiling demonstrates that PER2 dictates the specificity of PPARγ transcriptional activity. Indeed, lack of PER2 results in enhanced adipocyte differentiation of cultured fibroblasts. PER2 targets S112 in PPARγ, a residue whose mutation has been associated to altered lipid metabolism. Lipidomic profiling demonstrates that PER2 is necessary for normal lipid metabolism in white adipocyte tissue. Our findings support a scenario in which PER2 controls the pro-adipogenic activity of PPARγ by operating as its natural modulator, thereby revealing potential avenues of pharmacological and therapeutic intervention.
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影响因子：
9.2
作者：
Akhtar, RA;Reddy, AB;Kyriacou, CP
通讯作者：
Kyriacou, CP
影响因子：
3.9
作者：
Kopecky, J;Rossmeisl, M;Brauner, P
通讯作者：
Brauner, P
DOI：
10.1046/j.0014-2956.2002.02627.x
发表时间：
2002-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Rossmeisl, M;Barbatelli, G;Kopecky, J
通讯作者：
Kopecky, J
影响因子：
4.4
作者：
Hashimoto, T
通讯作者：
Hashimoto, T
影响因子：
5.3
作者：
Lee, C;Weaver, DR;Reppert, SM
通讯作者：
Reppert, SM