MACanalyzeR scRNAseq analysis tool reveals PPARγ^HIGH/GDF15^HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT

Author(s):Show less -

Ninni, Andrea ; Zaccaria, Fabio ; Verteramo, Luca ; Sciarretta, Francesca ; Silveira, Loreana Sanches ; Rosa-Neto, Jose Cesar ; Carotti, Simone ; Nevi, Lorenzo ; Grumati, Paolo ; Patel, Satish ; Carrera, Giulia ; Sgambato, Alessandro ; Lucchetti, Donatella ; Colella, Filomena ; Severi, Ilenia ; Senzacqua, Martina ; Giordano, Antonio ; Bernardini, Sergio ; Di Biagio, Claudia ; Tortolici, Flavia ; Rizzo, Giuseppe ; Cochain, Clement ; Chiurchiu, Valerio ; Ivanov, Stoyan ; Zhou, Beiyan ; Williams, Jesse W. ; Savage, David B. ; Aquilano, Katia ; Lettieri-Barbato, Daniele

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 16, n. 1, p. 16-pg., 2025-05-31.

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. (AU)

• FAPESP's process: 19/09679-2 - Characterization of PPARgamma knockout macrophages subpopulation in breast cancer model and the influence of moderate aerobic training
• Grantee: Loreana Sanches Silveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/06073-9 - Effect of clock genes over the immunometabolism and monocyte/macrophage differentiation in immunosenescence: the role of exercise training throughout life
• Grantee: José Cesar Rosa Neto
• Support Opportunities: Regular Research Grants