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, Clement Cochain, Valerio Chiurchiù, Stoyan Ivanov, Beiyan Zhou, Jesse W. Williams, David B. Savage, Katia Aquilano and Daniele Lettieri-Barbato ()
Additional contact information
Andrea Ninni: University of Rome Tor Vergata
Fabio Zaccaria: University of Rome Tor Vergata
Luca Verteramo: University of Rome Tor Vergata
Francesca Sciarretta: University of Rome Tor Vergata
Loreana Sanches Silveira: University of São Paulo (ICB1-USP)
José Cesar Rosa-Neto: University of São Paulo (ICB1-USP)
Simone Carotti: Università Campus Bio-Medico di Roma
Lorenzo Nevi: Università Campus Bio-Medico di Roma
Paolo Grumati: Telethon Institute of Genetics and Medicine
Satish Patel: University of Cambridge
Giulia Carrera: IRCCS Santa Lucia Foundation
Alessandro Sgambato: Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS
Donatella Lucchetti: Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS
Filomena Colella: Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS
Ilenia Severi: Marche Polytechnic University
Martina Senzacqua: Marche Polytechnic University
Antonio Giordano: Marche Polytechnic University
Sergio Bernardini: University of Rome Tor Vergata
Claudia Di Biagio: University of Rome Tor Vergata
Flavia Tortolici: University of Rome Tor Vergata
Giuseppe Rizzo: D16
Clement Cochain: D16
Valerio Chiurchiù: IRCCS Santa Lucia Foundation
Stoyan Ivanov: CNRS
Beiyan Zhou: University of Connecticut
Jesse W. Williams: University of Minnesota
David B. Savage: University of Cambridge
Katia Aquilano: University of Rome Tor Vergata
Daniele Lettieri-Barbato: University of Rome Tor Vergata

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60295-2

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