All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor
All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor
复制标题
DOI：
10.1128/mcb.01742-08
复制
发表时间：
2009-06-15
影响因子：
5.3
通讯作者：
Noy, Noa
中科院分区：
文献类型：
--
作者：
Berry, Daniel C.;Noy, Noa
全反式维甲酸（all-trans-retinoic acid，RA）的许多生物学活性是由配体激活的转录因子维甲酸受体（retinoic acid receptor，RAR）介导的，但这种激素也能激活核受体过氧化物酶体增殖激活受体β/δ（peroxisome proliferation activated receptor beta/delta，PPAR β/delta）。我们在这里表明，脂肪细胞分化伴随着RA信号的转变，在成熟的脂肪细胞中，允许RA激活RAR和PPAR β/δ，从而增强脂解和消耗脂质储存。使用饮食诱导的肥胖症小鼠模型的体内研究表明，肥胖症的发作伴随着脂肪PPAR β/δ表达和活性的下调。RA治疗肥胖小鼠诱导参与脂质稳态调节的PPAR β/δ和RAR靶基因的表达，导致体重减轻和胰岛素反应性改善。RA治疗也恢复了脂肪PPAR β/δ表达。这些数据表明，RA对肥胖和胰岛素抵抗的抑制主要由PPAR β/δ介导，并通过RAR的激活进一步增强。通过靶向两个核受体，RA可能是治疗和预防代谢综合征的独特有效的药物。
Many biological activities of all-trans-retinoic acid (RA) are mediated by the ligand-activated transcription factors termed retinoic acid receptors (RARs), but this hormone can also activate the nuclear receptor peroxisome proliferation-activated receptor beta/delta (PPAR beta/delta). We show here that adipocyte differentiation is accompanied by a shift in RA signaling which, in mature adipocytes, allows RA to activate both RARs and PPAR beta/delta, thereby enhancing lipolysis and depleting lipid stores. In vivo studies using a dietary-induced mouse model of obesity indicated that onset of obesity is accompanied by downregulation of adipose PPAR beta/delta expression and activity. RA treatment of obese mice induced expression of PPAR beta/delta and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPAR beta/delta expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPAR beta/delta and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome.