Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Adipocytes [mouse 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: adipo_cre X nuclei_Red mice were housed at room temperature, cold exposure 4 days and cold exposure 7 days. Mice adipocytes nuclei were isolated by FACS. Isolated nuclei were performed 10X single nuclei sequencing