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<p>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 <i>db/db</i> BAT LAMs, those in HFD BAT correlate with thermogenic gene expression and PPAR signaling activation. A distinct Pparg<sup>HIGH</sup> LAM subcluster progressively accumulates in thermogenically active BAT. Macrophage-specific Pparg depletion disrupts BAT thermogenesis, inducing a white-like phenotype and metabolic dysfunctions. Mechanistically, Pparg<sup>HIGH</sup> 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 Pparg<sup>HIGH</sup> LAMs as critical mediators of BAT homeostasis.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月31日

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  • 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,
  • Daniele Lettieri-Barbato

摘要

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.