MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT
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/mac...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60295-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850243244908085248 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Andrea Ninni |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c222936de52b410e95c85af4adc0b701 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c222936de52b410e95c85af4adc0b7012025-08-20T02:00:03ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-60295-2MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BATAndrea Ninni0Fabio Zaccaria1Luca Verteramo2Francesca Sciarretta3Loreana Sanches Silveira4José Cesar Rosa-Neto5Simone Carotti6Lorenzo Nevi7Paolo Grumati8Satish Patel9Giulia Carrera10Alessandro Sgambato11Donatella Lucchetti12Filomena Colella13Ilenia Severi14Martina Senzacqua15Antonio Giordano16Sergio Bernardini17Claudia Di Biagio18Flavia Tortolici19Giuseppe Rizzo20Clement Cochain21Valerio Chiurchiù22Stoyan Ivanov23Beiyan Zhou24Jesse W. Williams25David B. Savage26Katia Aquilano27Daniele Lettieri-Barbato28Department of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataImmunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo (ICB1-USP)Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo (ICB1-USP)Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di RomaMicroscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di RomaTelethon Institute of Genetics and MedicineMetabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of CambridgeLaboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia FoundationMultiplex Spatial Profiling Facility, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCSMultiplex Spatial Profiling Facility, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCSMultiplex Spatial Profiling Facility, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCSDepartment of Experimental and Clinical Medicine, Marche Polytechnic UniversityDepartment of Experimental and Clinical Medicine, Marche Polytechnic UniversityDepartment of Experimental and Clinical Medicine, Marche Polytechnic UniversityDepartment of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataInstitute of Experimental Biomedicine, University Hospital Würzburg, D16Institute of Experimental Biomedicine, University Hospital Würzburg, D16Laboratory of Resolution of Neuroinflammation, IRCCS Santa Lucia FoundationUniversité Côte d’Azur, CNRSDepartment of Immunology, School of Medicine, University of ConnecticutCenter for Immunology, University of MinnesotaMetabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of CambridgeDepartment of Biology, University of Rome Tor VergataDepartment of Biology, University of Rome Tor VergataAbstract 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.https://doi.org/10.1038/s41467-025-60295-2 |
| spellingShingle | 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 MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT Nature Communications |
| title | MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT |
| title_full | MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT |
| title_fullStr | MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT |
| title_full_unstemmed | MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT |
| title_short | MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT |
| title_sort | macanalyzer scrnaseq analysis tool reveals pparγhigh gdf15high lipid associated macrophages facilitate thermogenic expansion in bat |
| url | https://doi.org/10.1038/s41467-025-60295-2 |
| work_keys_str_mv | AT andreaninni macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT fabiozaccaria macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT lucaverteramo macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT francescasciarretta macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT loreanasanchessilveira macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT josecesarrosaneto macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT simonecarotti macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT lorenzonevi macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT paologrumati macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT satishpatel macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT giuliacarrera macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT alessandrosgambato macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT donatellalucchetti macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT filomenacolella macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT ileniaseveri macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT martinasenzacqua macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT antoniogiordano macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT sergiobernardini macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT claudiadibiagio macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT flaviatortolici macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT giusepperizzo macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT clementcochain macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT valeriochiurchiu macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT stoyanivanov macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT beiyanzhou macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT jessewwilliams macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT davidbsavage macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT katiaaquilano macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat AT danielelettieribarbato macanalyzerscrnaseqanalysistoolrevealspparghighgdf15highlipidassociatedmacrophagesfacilitatethermogenicexpansioninbat |