The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration [1]

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, the activation of thermogenic brown and beige adipocytes is linked to improved cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this adipocyte plasticity could help improving energy balance and weight loss. Here, we show that the long non-coding RNA (lncRNA) Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Searching for new human lncRNAs implicated in adipocyte biology we compared transcriptional profiles of human adipose tissues and cultured adipocytes and discovered that AATBC was enriched in thermogenic conditions. Using primary human adipocytes and immortalized human adipocytes we found that gain-of-function of AATBC enhanced the thermogenic phenotype whereas loss-of-function diminished this effect. The AATBC-mediated increase in mitochondrial respiration was linked to a more fragmented mitochondrial network and vice versa. While we found that AATBC is predominantly located in the nucleus, its effect on global transcription was only marginal. As AATBC is specific to humans, we expressed AATBC in adipose tissue of mice to study its systemic impact, which led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, body mass index and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans. hMADS cells treated with either scramble and siRNA AATBC for knockdown experiments or AV_GFP and AV_AATBC respectively for overexpression of the lncRNA AATBC

脂肪细胞是代谢与能量平衡的关键调控因子。尽管白色脂肪细胞功能障碍是肥胖相关疾病的标志性特征，但产热型棕色与米色脂肪细胞的活化与改善心脏代谢健康密切相关。由于脂肪细胞可通过在白色与产热表型间进行功能转换，动态适应环境信号，因此解析该脂肪细胞可塑性的分子机制，有望助力改善能量平衡与体重控制。本研究证实，长链非编码RNA（long non-coding RNA, lncRNA）膀胱癌细胞凋亡相关转录本（Apoptosis associated transcript in bladder cancer, AATBC）是人类特有的脂肪细胞可塑性调控因子。为挖掘参与脂肪细胞生物学过程的新型人类lncRNA，本研究对比了人类脂肪组织与培养脂肪细胞的转录组谱，发现AATBC在产热条件下表达富集。利用原代人脂肪细胞与永生化人脂肪细胞开展实验，研究发现AATBC的功能过表达可增强产热表型，而功能沉默则会削弱这一效应。AATBC介导的线粒体呼吸增强，与线粒体网络更高度碎片化相关，反之亦然。尽管研究发现AATBC主要定位于细胞核，但它对全局转录仅能产生微弱影响。由于AATBC为人类特有，本研究通过在小鼠脂肪组织中表达AATBC以探究其系统性影响，观察到小鼠血浆瘦素水平降低。有趣的是，这一关联在人类受试者中同样存在：脂肪组织中AATBC的表达水平与血浆瘦素、体质量指数及其他心脏代谢健康指标呈负相关。综上，AATBC是人类中一种新型的、与肥胖相关的脂肪细胞可塑性及线粒体功能调控因子。本研究中用于敲低实验的hMADS细胞分别用阴性对照siRNA与AATBC靶向siRNA处理，用于过表达实验的细胞则分别用AV_GFP与AV_AATBC感染，以实现lncRNA AATBC的过表达。