Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Adipocytes [human snRNA-seq]

Adipose tissue can recruit catabolic adipocytes which utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA-sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-beige and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-utilizing beige subpopulation is metabolically highly active and utilizes FCs to dissipate energy thus contributing to thermogenesis independent of UCP1. Furthermore, FC-beige adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals. Overall design: 10x single nuclei RNA seq of human subcutanous neck adipose tissue

脂肪组织可募集分解代谢型脂肪细胞，这类细胞可利用化学能量进行产热。该过程可通过两种途径实现：一是借助解偶联蛋白1（uncoupling protein 1, UCP1）完成解偶联呼吸，二是通过ATP依赖的无效循环（futile cycles, FCs）。但目前尚不明确这两条途径为何能够共存，因为二者均依赖线粒体膜电位。
本研究通过单细胞核RNA测序（single-nucleus RNA-sequencing）解析小鼠与人类皮下脂肪组织的细胞异质性，鉴定出至少两种独立的米色脂肪细胞（beige adipocytes）亚群：FC-米色脂肪细胞与UCP1-米色脂肪细胞。尤为重要的是，本研究证实依赖无效循环的米色脂肪亚群代谢活性极高，可通过无效循环消耗能量，从而实现不依赖UCP1的产热过程。
此外，人类体内的FC-米色脂肪细胞是维持全身能量稳态的关键调控因子，且与葡萄糖代谢及抗肥胖表型密切相关。
综上，本研究发现了一类非经典产热脂肪细胞亚群，该亚群或可作为哺乳动物体内能量稳态的重要调节者。
实验整体设计：对人类颈部皮下脂肪组织开展10x单细胞核RNA测序。