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MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT

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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
Número total de Autores: 29
Tipo de documento: Artigo Científico
Fonte: NATURE COMMUNICATIONS; v. 16, n. 1, p. 16-pg., 2025-05-31.
Resumo

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)

Processo FAPESP: 19/09679-2 - Caracterização da subpopulação de macrófagos com deleção de PPARgamma em modelo de câncer de mama e a influência do treinamento aeróbio moderado
Beneficiário:Loreana Sanches Silveira
Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 22/06073-9 - Efeito dos clock genes sobre a regulação do imunometabolismo e diferenciação de monócitos/macrófagos durante a imunossenescência: o papel do treinamento físico ao longo da vida
Beneficiário:José Cesar Rosa Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular