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

Nat Commun. 2025 May 31;16(1):5063. doi: 10.1038/s41467-025-60295-2.

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.

MeSH terms

  • Adipose Tissue, Brown* / metabolism
  • Animals
  • Diet, High-Fat
  • Growth Differentiation Factor 15* / genetics
  • Growth Differentiation Factor 15* / metabolism
  • Humans
  • Lipid Metabolism
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR gamma* / genetics
  • PPAR gamma* / metabolism
  • RNA-Seq / methods
  • Sequence Analysis, RNA / methods
  • Single-Cell Analysis / methods
  • Single-Cell Gene Expression Analysis
  • Thermogenesis* / genetics

Substances

  • PPAR gamma
  • Growth Differentiation Factor 15
  • Gdf15 protein, mouse
  • Pparg protein, mouse