Tissue specific regulation of BMAL1 gene by dietary fat

脂肪细胞扮演着重要的代谢角色，不仅作为大量的能量储备，而且还分泌调节代谢活动的激素和细胞因子。脂肪细胞的代谢活动和昼夜节律之间的联系早已被研究；例如，众所周知，葡萄糖和脂肪的动态平衡表现出昼夜节律的变化。最近，我们报道白色脂肪组织含有功能分子钟，几种脂肪细胞因子，包括瘦素和纤溶酶原激活物抑制物-1的表达显示出昼夜节律(Ayagi，et。艾尔JHS 2005)。因此，分子时钟可能在脂肪细胞代谢活动的调节中发挥重要作用。BMal1是昼夜节律的主要成分，在体内和体外成熟的脂肪细胞中大量表达。该转录因子调节脂肪细胞中几个与脂肪形成有关的因子的表达，如SREBP-1(Shimba，et.艾尔PNAS 2005)。此外，BMAL1KO小鼠也表现出si…表型脂肪组织减少更明显，而KO小鼠的肝脏与野生型一样完整。BMAL1的这些特性引导我们研究该因子在脂肪细胞中的特定作用。在这项研究中，我们首先研究了膳食脂肪对成熟脂肪细胞BMAL1表达和功能的影响。对高脂饮食的挑战导致小鼠脂肪组织中BMal1mRNA的显著诱导。有趣的是，高脂饮食诱导的昼夜节律基因只在脂肪组织中观察到，而在其他被测试的组织中没有观察到。这种脂肪组织特异性诱导BMal1表达的同时，其靶基因如PER和PAI-1的表达增强。TB决定饮食脂肪是否对BMal1的表达有直接影响，用不同的饱和、不饱和和反式脂肪酸处理培养的脂肪细胞，并检测其中一种脂肪酸显著增加培养的脂肪细胞的BMal1 mRNA的水平，但在原代肝细胞中没有。抑制脂肪酸代谢减弱了对BMal1表达的影响。脂肪酸的初步代谢产物增加了BMal1mRNAs的水平，最后，脂肪酸处理诱导了培养的脂肪细胞中昼夜节律基因的周期性表达。这些结果表明，膳食脂肪酸可以调节脂肪细胞特定的昼夜节律机制。较少

Adipocytes play essential metabolic roles not only serving as massive energy reserves but also secreting hormones and cytokines that regulate metabolic activities. The link between metabolic activity in adipocytes and circadian rhythm has long been studied ; e.g. glucose and lipid homeostasis are well known to exhibit circadian variation. More recently, we reported that white adipose tissue contains functional molecular clock and that expression of several adipocytokines, including leptin, and plasminogen activator inhibitor-1 display circadian rhythm (Aoyagi, et. al. JHS 2005). Therefore, molecular clock may play important roles in the regulation of metabolic activity in adipocytes. BMAL1, a master component of circadian rhythm, is abundantly expressed in mature adipocytes in vivo and in vitro. This transcription factor regulates the expression of several factors involved in lipogenesis in adipocytes such as SREBP-1 (Shimba, et. al. PNAS 2005). Also, BMAL1 KO mice show phenotype of si … More gnificant reduction of adipose tissue, while the liver in KO mice is as intact as that in wild type. These characteristics of BMAL1 lead us to study the adipocytes-specific roles of this factor. In this study, we first examine the effects of dietary fat on BMAL1 expression and functions in mature adipocytes. The challenge to high fat diet results in significant induction of Bmal1 mRNA in mice adipose tissue. Interestingly, the induction of circadian gene by high-fat diet is observed only in adipose tissue, but not in other tissues tested. This adipose tissue specific induction of Bmal1 expression accompanied with enhanced expression of its targets genes such as Per and PAI-1. Tb determine whether dietary fats have a direct impact on Bmal1 expression, cultured adipocytes were treated with various saturated, unsaturated, and trans fatty acids and examined levels of Bmal1 mRNA One of the fatty acids significantly increased Bmal1 mRNA level in cultured adipocytes but not in primary hepatocytes. Inhibition of the fatty acid metabolism diminished the effect on Bmal1 expression. Tentative metabolites of the fatty acid increased Bmal1 mRNAlevel Finally, the fatty acid-treatment induced cyclic expression of circadian genes in cultured adipocytes. These results suggest that dietary fatty acids can modulate adipocytes specific circadian rhythm machinery. Less