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

Author

Listed:
  • Andrea Ninni

    (University of Rome Tor Vergata
    University of Rome Tor Vergata)

  • Fabio Zaccaria

    (University of Rome Tor Vergata
    University of Rome Tor Vergata)

  • Luca Verteramo

    (University of Rome Tor Vergata
    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
    University Federico II)

  • Satish Patel

    (University of Cambridge)

  • Giulia Carrera

    (IRCCS Santa Lucia Foundation
    University of Rome Tor Vergata)

  • Alessandro Sgambato

    (Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS
    Università Cattolica del Sacro Cuore)

  • Donatella Lucchetti

    (Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS
    Università Cattolica del Sacro Cuore)

  • Filomena Colella

    (Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS)

  • Ilenia Severi

    (Marche Polytechnic University)

  • Martina Senzacqua

    (Marche Polytechnic University)

  • Antonio Giordano

    (Marche Polytechnic University
    IRCSS INRCA
    Marche Polytechnic University-United Hospitals)

  • 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
    INSERM U970)

  • Valerio Chiurchiù

    (IRCCS Santa Lucia Foundation
    National Research Council)

  • Stoyan Ivanov

    (CNRS)

  • Beiyan Zhou

    (University of Connecticut)

  • Jesse W. Williams

    (University of Minnesota
    University of Minnesota)

  • David B. Savage

    (University of Cambridge)

  • Katia Aquilano

    (University of Rome Tor Vergata)

  • Daniele Lettieri-Barbato

    (University of Rome Tor Vergata)

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.

Suggested Citation

  • 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 , 2025. "MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60295-2
    DOI: 10.1038/s41467-025-60295-2
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