Role of PPARγ, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action:: view from the chair
Role of PPARγ, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action:: view from the chair
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DOI：
10.1038/sj.ijo.0802904
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发表时间：
2005-03-01
影响因子：
4.9
通讯作者：
Berger, JP
中科院分区：
文献类型：
--
作者：
Berger, JP
过氧化物酶体增殖物激活受体(PPAR)是核受体的一个亚家族。1三种PPAR亚型g、a和d由三个独立的基因编码，是调节代谢动态平衡的营养感受器。它们是配体调节的转录因子，其主要生理作用是通过改变基因表达来调节的。PPAR与RXR异源二聚，然后与基因调节域中的过氧化物体增殖物反应元件结合。当被激动剂结合时，PPAR的构象发生变化，从而与重塑染色质并与细胞转录机制通信的共激活物高亲和力结合。结果，转录启动被诱导，PPAR反应转录本的水平增加。PPARG在脂肪组织中高表达。PPARg的激活通过调节众多调控脂肪生成、脂肪摄取和脂肪代谢的基因，诱导脂肪细胞分化和脂肪细胞的脂肪堆积。值得注意的是，PPARg缺失的细胞不能分化为脂肪细胞，脂肪特异性去除PPARg会导致脂肪细胞数量减少和肥胖度降低。噻唑烷二酮(TZD)胰岛素增敏剂是PPARg配体；体内降糖效果与其受体激动剂的效力相关。PPARg激动剂的胰岛素增敏作用源于它们能够通过减少脂肪细胞的脂解来降低循环中的游离脂肪酸，调节调节胰岛素作用的蛋白质的表达，并作为脂肪重建剂将脂肪从脂解的内脏脂肪库引导到含有胰岛素反应性小脂肪细胞的皮下脂肪组织中。2PPARg辅活化子-1(PGC-1)是一种转录辅活化子，它最初被鉴定是因为它与其得名的受体具有高亲和力，Pere Puigserver讨论了这一问题。PPARg只有与PGC-1相互作用，激活线粒体UCP-1转录，才能诱导棕色脂肪细胞分化。3为了在棕色脂肪细胞中诱导完整的生热反应所需的所有基因的表达，PGC-1还作为其他核受体的辅助激活因子，包括PPARa、TR、RAR和ERRA。此外，当需要生热时，交感神经系统通过激活b-肾上腺素受体转导通路上调和稳定PGC-1。PGC-1还在骨骼肌的分化和代谢活动中发挥关键作用，骨骼肌是运动中能量利用的主要部位。4共激活剂足以诱导线粒体生物发生和I型(慢抽动)肌的产生。钙信号级联通过激活转录因子来提高PGC-1肌肉的表达，转录因子在辅活化子的启动子中具有反应元件。肌肉中PGC-1的药理激活可能会减轻肥胖。在空腹和糖尿病状态下，PGC-1不仅诱导脂质分解代谢，而且还诱导肝脏糖异生。5胰高血糖素通过cAMP依赖的信号转导途径，与糖皮质激素信号通路协同作用，增加PGC-1的表达；然后，辅活化子与几个转录因子相互作用，增强关键的糖异生酶的表达。抑制PGC-1激活的肝糖生成可用于治疗糖尿病高血糖。斯蒂芬·法默详细介绍了转录因子和调控脂肪形成复杂过程的信号通路之间的几个重要相互作用。C/EBpb和C/EBPd与糖皮质激素协同诱导PPARg的表达，进而诱导…
The peroxisome proliferator-activated receptors (PPARs) compose a nuclear receptor subfamily. 1 The three PPAR isoforms, g, a and d, which are encoded by three separate genes, are nutrient sensors that regulate metabolic homeostasis. They are ligand-regulated transcription factors whose main physiological actions are mediated by altering gene expression. PPARs heterodimerize with RXR, then bind to peroxisome proliferator response elements in regulatory domains of genes. Upon being bound by agonists, PPAR conformation is changed such that it binds with high affinity to coactivators that remodel chromatin and communicate with the cellular transcriptional machinery. As a result, transcriptional initiation is induced and the levels of PPAR-responsive transcripts increase. PPARg is highly expressed in adipose tissue. Activation of PPARg induces adipocyte differentiation and lipid accumulation by adipocytes by modulating numerous genes regulating adipogenesis, lipid uptake and lipid metabolism. Notably, PPARg null cells cannot differentiate into adipocytes and the adipose-specific ablation of PPARg results in adipocyte hypocellularity and reduced adiposity. Thiazolidinedione (TZD) insulin-sensitizing agents are PPARg ligands; their antidiabetic efficacy in vivo has been shown to correlate with their receptor agonist potency. The insulin-sensitizing action of PPARg agonists results from their ability to lower circulating free fatty acids by decreasing adipocyte lipolysis, regulate the expression of proteins that modulate insulin action and serve as adipose remodeling agents that direct lipids away from lipolytic visceral fat depots and into subcutaneous fat tissue containing small, insulin-responsive adipocytes. 2PPARg coactivator-1 (PGC-1), a transcriptional coactivator that was first identified as a result of its high affinity for the receptor from which it takes its name, was discussed by Pere Puigserver. Only by interacting with PGC-1 and activating the transcription of mitochondrial UCP-1 can PPARg induce brown adipocyte differentiation. 3 To induce the expression of all the genes required for a complete thermogenic response in brown adipocytes, PGC-1 also serves as a coactivator of other nuclear receptors including PPARa, TR, RAR and ERRa. Additionally, when thermogenesis is required, PGC-1 is upregulated and stabilized by the sympathetic nervous system via activation of b-adrenoreceptor transduction pathways. PGC-1 also plays a critical role in the differentiation and metabolic activity of skeletal muscle, a major site of energy utilization during exercise. 4 The coactivator is sufficient for the induction of mitochondria biogenesis and the generation of type 1 (slow twitch) muscle. Calcium signaling cascades elevate PGC-1 muscle expression by activating transcription factors that have response elements in the coactivator’s promoter. Pharmacological activation of PGC-1 in muscle might mitigate obesity. PGC-1 not only induces lipid catabolism but also hepatic gluconeogenesis during the fasted and diabetic states. 5 Glucagon increases PGC-1 expression by cAMP-dependent transduction pathways that synergize with glucocorticoid signaling cascades; the coactivator then interacts with several transcription factors to augment expression of key gluconeogenic enzymes. Inhibition of PGC-1-activated hepatic glucose production may serve as treatment for diabetic hyperglycemia. Several important interactions between transcription factors and signaling pathways that regulate the complex process of adipogenesis were detailed by Stephen Farmer. C/EBPb and C/EBPd cooperate with glucocorticoids to induce expression of PPARg, which in turn is …