Macrophages as niche architects of adipose tissue plasticity

Adipose tissue expansion during obesity depends on the precise regulation of adipocyte stem cells (ASCs). While inflammatory macrophages in obese fat are well-characterized⁽²⁾, how resident macrophage subsets influence ASC differentiation in lean tissue has remained elusive. The authors identified a rare population of CD209b⁺LYVE1⁺ septal macrophages (sATMs) specifically localized within the intralobular septa of white adipose tissue (WAT)—a collagen- and hyaluronan-rich microenvironment that also harbors CD26⁺ multipotent ASCs. These macrophages are predominantly embryonically derived and maintain their niche identity over time.

sATMs maintain white adipocyte fate and limit beiging

Through a series of innovative depletion models and macrophage-specific TGFβ1 gene knockouts, the researchers demonstrated that sATMs are essential for maintaining the white adipogenic fate of ASCs. Their depletion led to a marked increase in thermogenic beige adipocyte differentiation, improved glucose metabolism, and protection against high-fat diet–induced obesity. Mechanistically, sATMs deliver TGFβ1 signals to CD26+ ASCs, promoting their commitment to the white adipocyte lineage. Loss of this signal—whether through sATM ablation or conditional deletion of TGFβ1 in sATMs—redirected stem cell fate, enhanced thermogenesis, and boosted systemic energy expenditure.

Spatial immunometabolism: the septum as a regulatory niche

This study reveals that the adipose septum functions as more than a structural partition—it is a spatially confined regulatory niche where immune and progenitor cells interact. The authors describe this macrophage–stem cell interaction as a functional unit that governs adipose remodeling in response to metabolic demands. This concept echoes similar niche paradigms in regenerative tissues and points to a broader role for subtissular macrophages in instructing local stem cell fate.

Translational relevance in human adipose tissue

Crucially, the findings extend to human biology. Using scRNA-seq, CODEX multiplex imaging, and antibody-based profiling, the authors identified human septal macrophages (hsATMs) with similar phenotypes and spatial localization. These macrophages were found in close proximity to human CD26⁺ ASCs and exhibited active TGFβ1 signaling, suggesting a conserved mechanism that may regulate adipose plasticity and metabolic health in humans.

Implications and future directions

By uncovering a macrophage-controlled signaling axis that dictates ASC fate via spatially confined TGFβ1 delivery, this study redefines the rules of immune-stromal crosstalk in tissue remodeling. Targeting the septal macrophage niche or it‘s signaling pathways could offer new therapeutic avenues to enhance energy expenditure, promote WAT beiging, and mitigate obesity and related metabolic disorders. The demonstration of a conserved septal macrophage–stem cell unit in humans reinforces the translational value of this discovery.

This seminal work exemplifies the power of spatial biology in decoding cellular interactions within complex tissues and provides a conceptual framework for manipulating macrophage niches in regenerative and metabolic medicine.

Xiaotong Yu and Yanan Hu, PhD students from the laboratory of Svetoslav Chakarov at the Shanghai Institute of Immunology, are the co-first authors of the paper. Svetoslav Chakarov and Prof. Florent Ginhoux (Visiting Professor at the Shanghai Institute of Immunology; Gustave Roussy Institute, France) served as co-corresponding authors.

The authors are grateful for the strong support provided by Prof. Bing Su (Shanghai Institute of Immunology), Dr. Ziyi Li (Suzhou Institute of Systems Medicine), and Prof. Nicolas Venteclef (Université Paris Cité, France).

This study was supported by funding from the Ministry of Science and Technology's Key R&D Program, the National Natural Science Foundation of China, with technical support provided by the flow cytometry and imaging platforms of the Shanghai Institute of Immunology, as well as the public technology platform and experimental animal center of the Basic Medical College at Shanghai Jiao Tong University School of Medicine.

DOI: 10.1126/science.adg1128

References:

1、S. Chakarov et al., Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363,  (2019).

2、S. Chakarov, C. Bleriot, F. Ginhoux, Role of adipose tissue macrophages in obesity-related disorders. J Exp Med 219,  (2022).

Svetoslav Chakarov, Principal Investigator and Doctoral Supervisor at the Shanghai Jiao Tong University School of Medicine / Shanghai Institute of Immunology, is a recipient of the National High-Level Talent Program and holds the Shanghai Eastern Scholar Distinguished Professorship. His research group is dedicated to understand the heterogeneity of myeloid cells, their differentiation pathways and how their sub-tissular niche of residence dictates their tissue specific metabolic functions. He has published original studies as first or corresponding author in leading international journals including Science（2019, 2025）Immunity, J. Exp. Med. and PNAS. He currently heads projects funded by the National Natural Science Foundation of China, has been awarded the Excellent Young Scientists Fund (Overseas) by the NSFC, Research Fund for International Scientists, participates as a key member in Ministry of Science and Technology National Key R&D Program of China, and has received financial support under the Shanghai Foreign Expert Program.