Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes

Adipose tissue can recruit catabolic adipocytes that 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-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-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. [Display omitted] •snRNA-seq reveals distinct subpopulations of adipocytes in mouse ingWAT at RT and CE•A novel subpopulation, P2 adipocytes, functions as thermogenic cells•P2 adipocytes plausibly utilize futile cycles for UCP1-independent thermogenesis•P2-like human adipocyte is associated with energy expenditure and metabolic health Using the snRNA-seq of iWAT from mice at different temperatures, Wang et al. identified P2 adipocytes that perform futile cycling-mediated thermogenesis in mice. Consistently, the prevalence of an analogous population in human subcutaneous adipose tissue (H-Ad-3) is correlated with energy expenditure and metabolic health.