MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT
Andrea Ninni, Fabio Zaccaria, Luca Verteramo, Francesca Sciarretta, Loreana Sanches Silveira, José Cesar Rosa Neto, Simone Carotti, Lorenzo Nevi, Paolo Grumati, Satish Patel, Giulia Carrera, Alessandro Sgambato, Donatella Lucchetti, Filomena Colella, Ilenia Severi, Martina Senzacqua, Antonio Giordano, Sergio Bernardini, Claudia Di Biagio, Flavia Tortolici, Giuseppe Rizzo, Clément Cochain, Valerio Chiurchiù, Stoyan Ivanov, Beiyan Zhou, Jesse W. Williams, David B. Savage, Katia Aquilano, Daniele Lettieri‐Barbato
Abstract
Macrophages are key regulators of adipose tissue plasticity. Obesity impairs brown adipose tissue (BAT) function in humans, yet macrophage-mediated mechanisms remain elusive. Here, we introduce MACanalyzeR, a single-cell RNA sequencing (scRNAseq) tool designed for comprehensive monocyte/macrophage metabolic profiling. Applying MACanalyzeR to BAT from obese male murine models (db/db and HFD-fed mice), we identify lipid-associated macrophages (LAMs) with foamy characteristics. Unlike db/db BAT LAMs, those in HFD BAT correlate with thermogenic gene expression and PPAR signaling activation. A distinct PpargHIGH LAM subcluster progressively accumulates in thermogenically active BAT. Macrophage-specific Pparg depletion disrupts BAT thermogenesis, inducing a white-like phenotype and metabolic dysfunctions. Mechanistically, PpargHIGH LAMs secrete GDF15, a key regulator of BAT identity and lipid metabolism under high-energy demand. Our study establishes MACanalyzeR as a powerful tool for immunometabolic interrogation and identifies PpargHIGH LAMs as critical mediators of BAT homeostasis. The homeostasis and function of adipose tissue are tightly regulated by immune cells, with macrophages playing a pivotal role. Here the authors show that PpargHIGH macrophages positively enhance brown adipose tissue thermogenesis through GDF15.