Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Mol Metab. 2018 Aug;14:60-70. doi: 10.1016/j.molmet.2018.06.005. Epub 2018 Jun 8.
Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of adipocyte differentiation and gene expression. However, their significance in adipose tissue metabolism and physiology has not been demonstrated in vivo. We previously identified Blnc1 as a conserved lncRNA regulator of brown and beige adipocyte differentiation. In this study, we investigated the physiological role of Blnc1 in thermogenesis, adipose remodeling and systemic metabolism.
We generated fat-specific Blnc1 transgenic and conditional knockout mouse strains and investigated how adipocyte Blnc1 levels are causally linked to key aspects of metabolic health following diet-induced obesity. We performed studies using cultured adipocytes to establish cell-autonomous role of Blnc1 in regulating adipocyte gene programs.
Blnc1 is highly induced in both brown and white fats from obese mice. Fat-specific inactivation of Blnc1 impairs cold-induced thermogenesis and browning and exacerbates obesity-associated brown fat whitening, adipose tissue inflammation and fibrosis, leading to more severe insulin resistance and hepatic steatosis. On the contrary, transgenic expression of Blnc1 in adipose tissue elicits the opposite and beneficial metabolic effects, supporting a critical role of Blnc1 in driving adipose adaptation and homeostatic remodeling during obesity. Mechanistically, Blnc1 cell-autonomously attenuates proinflammatory cytokine signaling and promotes fuel storage in adipocytes through its protein partner Zbtb7b.
This study illustrates a surprisingly pleiotropic and dominant role of lncRNA in driving adaptive adipose tissue remodeling and preserving metabolic health.
长链非编码 RNA（lncRNA）正在成为调节脂肪细胞分化和基因表达的强大调控因子。然而，它们在脂肪组织代谢和生理学中的重要性尚未在体内得到证明。我们之前发现 Blnc1 是一种保守的 lncRNA，可调节棕色和米色脂肪细胞的分化。在这项研究中，我们研究了 Blnc1 在产热、脂肪重塑和全身代谢中的生理作用。
我们生成了脂肪特异性 Blnc1 转基因和条件敲除小鼠品系，并研究了脂肪细胞 Blnc1 水平如何在饮食诱导肥胖后与代谢健康的关键方面因果相关。我们使用培养的脂肪细胞进行研究，以确定 Blnc1 在调节脂肪细胞基因程序中的细胞自主性作用。
肥胖小鼠的棕色和白色脂肪中 Blnc1 的表达均显著上调。脂肪特异性 Blnc1 失活会损害冷诱导的产热和棕色化，并加剧肥胖相关的棕色脂肪白化、脂肪组织炎症和纤维化，导致更严重的胰岛素抵抗和肝脂肪变性。相反，脂肪组织中转基因表达 Blnc1 会产生相反的有益代谢作用，支持 Blnc1 在肥胖期间驱动脂肪适应性和稳态重塑的关键作用。机制上，Blnc1 通过其蛋白伴侣 Zbtb7b 自主减弱促炎细胞因子信号并促进脂肪细胞的燃料储存。
这项研究说明了 lncRNA 在驱动适应性脂肪组织重塑和维持代谢健康方面具有惊人的多效性和主导作用。
