Search

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. [ABSTRACT FROM AUTHOR]

Summary Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo , whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism. Graphical Abstract Highlights • The mevalonate pathway is important for adipose tissue browning in mouse and human • Statin use is inversely correlated with brown fat activity in humans • Geranylgeranylation of small GTP-binding proteins promotes adipocyte browning • Small GTP-binding proteins regulate F-actin formation and YAP1/TAZ stability Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning. [ABSTRACT FROM AUTHOR]