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Tissue specific regulation of BMAL1 gene by dietary fat

膳食脂肪对 BMAL1 基因的组织特异性调节

基本信息

批准号：
18590077
负责人：
SHIMBA Shigeki
金额：
$ 2.57万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590077/
关键词：
BMAL1 adipocytes metabolic syndrome

项目摘要

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

脂肪细胞在代谢中起着重要的作用，不仅是能量的储备，还能分泌调节代谢活动的激素和细胞因子。脂肪细胞中的代谢活动与昼夜节律之间的联系已经研究了很久;例如，众所周知，葡萄糖和脂质稳态表现出昼夜变化。最近，我们报道了白色脂肪组织含有功能性分子钟，并且几种脂肪细胞因子（包括瘦素和纤溶酶原激活物抑制剂-1）的表达显示昼夜节律（Aoyagi，et. JHS 2005）。因此，分子钟可能在脂肪细胞代谢活动的调节中发挥重要作用。BMAL 1是昼夜节律的主要组成部分，在体内和体外成熟脂肪细胞中大量表达。该转录因子调节参与脂肪细胞中脂肪生成的几种因子的表达，例如SREBP-1（Shimba，et.等人，PNAS 2005）。此外，BMAL 1基因敲除小鼠表现出单克隆抗体的表型。 ...更多信息脂肪组织显著减少，而KO小鼠的肝脏与野生型一样完整。BMAL 1的这些特征使我们研究了该因子在脂肪细胞中的特异性作用。在这项研究中，我们首先研究了膳食脂肪对成熟脂肪细胞中BMAL 1表达和功能的影响。高脂饮食刺激导致小鼠脂肪组织中Bmal 1 mRNA的显著诱导。有趣的是，高脂饮食仅在脂肪组织中观察到昼夜节律基因的诱导，而在测试的其他组织中没有观察到。这种脂肪组织特异性诱导Bmal 1表达伴随着其靶基因如Per和派-1的表达增强。为了确定膳食脂肪是否对Bmal 1表达有直接影响，用各种饱和、不饱和和反式脂肪酸处理培养的脂肪细胞，并检测Bmal 1 mRNA的水平。其中一种脂肪酸显著增加培养的脂肪细胞中的Bmal 1 mRNA水平，但在原代肝细胞中不增加。脂肪酸代谢的抑制减弱了对Bmal 1表达的影响。脂肪酸的初步代谢产物增加Bmal 1 mRNA水平最后，脂肪酸处理诱导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异性昼夜节律机制。少