Adipocyte NR1D1 dictates adipose tissue expansion during obesity.
Adipocyte NR1D1 dictates adipose tissue expansion during obesity.
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DOI：
10.7554/elife.63324
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发表时间：
2021-08-05
期刊：
影响因子：
7.7
通讯作者：
Bechtold DA
中科院分区：
文献类型：
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作者：
Hunter AL;Pelekanou CE;Barron NJ;Northeast RC;Grudzien M;Adamson AD;Downton P;Cornfield T;Cunningham PS;Billaud JN;Hodson L;Loudon AS;Unwin RD;Iqbal M;Ray DW;Bechtold DA
生物钟成分Nr1d1(Reflbα)被认为是脂代谢的主要调节因子，Nr1d1的全局缺失驱动白色脂肪组织(WAT)脂肪生成和肥胖的失调。然而，在脂肪细胞选择性缺失(Nr1d1Flox2-6：AdipoqCre)下没有观察到类似的表型，转录图谱表明，在基础条件下，NR1D1调节的直接靶点是有限的，包括生物钟和胶原动力学。在高脂饮食(HFD)喂养下，Nr1d1Flox2-6：AdipoqCre小鼠确实表现出严重的肥胖，但没有伴随着Wat的炎症和纤维化。Wat NR1D1cstrome与差异基因表达的整合揭示了NR1D1对代谢过程的广泛控制，而NR1D1在肥胖状态下并未被掩盖。脂肪细胞NR1D1并不驱动WAT脂肪生成的预期每日节律，而是调节WAT活动以响应代谢状态的变化。重要的是，NR1D1在脂肪细胞中的作用对于肥胖相关的Wat病理和胰岛素抵抗的发展至关重要。
The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.