Septal LYVE1+ macrophages control adipocyte stem cell adipogenic potential.
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| Title: | Septal LYVE1+ macrophages control adipocyte stem cell adipogenic potential. |
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| Authors: | Yu, Xiaotong, Hu, Yanan, Lim, Hwee Ying, Li, Ziyi, Jaitin, Diego Adhemar, Yang, Katharine, Kong, Wan Ting, Xu, Jiaqian, Bejarano, David Alejandro, Bied, Mathilde, Orliaguet, Lucie, Rengasamy, Gowshika, Chow, Zachary, Lee, Christopher Zhe Wei, Lum, Josephine, Tian, Jing, Zhang, Xiao-Meng, Liu, Honghao, Tan, Shu Wen, Chen, Jinmiao |
| Source: | Science. 8/28/2025, Vol. 389 Issue 6763, p1-19. 19p. |
| Subjects: | Fat cells, Macrophages, Phenotypes, Obesity, Transcriptomes |
| Abstract: | Tissue macrophages reside in anatomically distinct subtissular niches that shape their identity and function. In white adipose tissue (WAT), we identified three macrophage populations with distinct localization, turnover, and phenotypes. Septal adipose tissue macrophages (sATMs), marked by CD209b and lymphatic vessel endothelial hyaluronan receptor 1, were long-lived and positioned in close proximity to adipocyte stem cells (ASCs) within the WAT septum. Within this shared niche, sATMs instructed the differentiation of ASCs into white adipocytes through transforming growth factor–β1 (TGFβ1). Depletion of sATMs, or the selective loss of TGFβ1 within tissue-resident macrophages, redirected ASC fate toward thermogenic adipocytes, enhancing WAT beiging and protecting against diet-induced obesity. These findings highlight the role of a discrete, anatomically defined macrophage population that governs ASC fate and orchestrates adipose tissue expansion. Editor's summary: In addition to their role in host defense, macrophages contribute to the development and remodeling of tissues. Yu et al. characterized macrophages found in the adipose tissue of mice on the basis of their gene expression, localization within the tissue, and developmental origin. A subset of macrophages localized in the same tissue microenvironment as adipocyte stem cells and promoted their differentiation into white adipocytes. Specific deletion of these macrophages promoted the differentiation of thermogenic, rather than white, adipocytes and prevented mice from becoming obese in response to a high-fat diet. A similar population of cells were identified in human adipose tissue. —Sarah H. Ross INTRODUCTION: Adipose tissue (AT) is a dynamic organ composed of lipid-storing adipocytes, adipocyte stem cells (ASCs), and resident immune cells. Macrophages are among the most abundant immune cells in AT and, depending on the physiological context, can maintain tissue function or drive inflammation. Prior studies have characterized inflammatory macrophages in obesity, but the identity and role of resident macrophages under steady state and their interaction with stromal populations is poorly understood. Recent evidence indicates that macrophage specialization may extend beyond tissue-level niches into more refined "subtissular" compartments. Whether such localization impacts AT macrophage identity and function has remained unresolved. RATIONALE: We hypothesized that subtissular macrophage niches within AT serve as instructive hubs for ASC fate specification. Using spatial, transcriptomic, and functional analyses in mice and humans, we investigated whether specific macrophage subsets localized to defined AT compartments, interacted with progenitor cells, and regulated adipogenesis. RESULTS: We defined three distinct AT macrophage (ATM) populations based on their subtissular localization and molecular signatures: parenchymal (pATMs), capsular (cATMs), and septal (sATMs). The sATMs, characterized by the expression of CD209b and LYVE1 (CD209b+LYVE1+), were selectively enriched in intralobular septa, a dense collagen- and hyaluronan-rich structure traversing adipocyte lobules, in close proximity to early CD26 expressing ASCs (ASCsCD26+). These sATMs were primarily embryonic-derived, long-lived, and distinct from monocyte-derived, inflammation-associated ATMs. In response to a high-fat diet (HFD) challenge, sATMs remained spatially restricted and resisted monocyte replacement whereas pATMs increased in number through both local proliferation and monocyte influx. Selective genetic depletion of sATMs using a Cd209b-driven DTR model enhanced thermogenesis, WAT beiging, increased oxygen consumption, and protection from HFD-induced obesity, independently of food intake. These mice also exhibited improved glucose tolerance and insulin sensitivity, along with reduced liver steatosis. Single-cell and bulk RNA-seq of AT stromal fractions identified ASCsCD26+ as highly proliferative, early progenitors localized in the septa. Upon sATM depletion, ASCCD26+ frequency declined, and their transcriptional profiles shifted toward a thermogenic, brown/beige fate. Ligand-receptor interaction modeling pinpointed TGFβ1 as a signal derived from sATMs that acted on ASCs via TGFβR1/2. Specific deletion of Tgfb1 in LYVE1+ or TIM4+ macrophages in vivo recapitulated sATM depletion phenotypes. In vitro, ASCsCD26+ from TGFβ1-deficient mice showed impaired white adipogenic differentiation and greater capacity for thermogenic conversion. We identified a conserved population of CD206+LYVE1+ human septal ATMs (hsATMs) in obese patients, expressing high levels of TGFB1 and residing adjacent to CD26+CD55+ early human ASCs (hASCsCD26+). Multiplex imaging confirmed close physical proximity between hsATMs and hASCsCD26+ within septal zones of human WAT. CONCLUSION: Subtissular localization may be a critical determinant of macrophage function and positions the adipose septum as a discrete immunometabolic niche essential for tissue remodeling. Our findings define a spatially confined niche containing resident macrophages and stem cells within the septum of white adipose tissue that governs adipose tissue plasticity and energy balance. Septal ATMs provided localized TGFβ1 signals that direct early adipocyte progenitors toward white adipocyte differentiation while restraining thermogenic potential. Depletion or functional inactivation of this sATM niche shifted the ASC fate toward beige adipogenesis, enhanced energy expenditure, and conferred systemic metabolic benefits in obesity. This regulatory axis between septal resident macrophages and adipocyte progenitors develops understanding of immune-stromal cross-talk in metabolic tissues. Targeting the sATM–TGFβ1–ASC axis may offer therapeutic strategies to boost WAT beiging and counteract obesity and insulin resistance without triggering inflammation. Spatially distinct macrophage niches govern adipogenesis.: White fat is organized into three anatomical compartments—septum, capsule, and parenchyma—each containing distinct populations of adipose tissue macrophages (ATMs). Septal macrophages (sATMs) are positioned in close contact with a population of early fat stem cells expressing CD26 (ASCsCD26+) within the septal niche. This spatial association enables sATMs to guide stem cell fate through TGFβ1 signaling, promoting the formation of energy-storing white fat cells. [Figure created using BioRender.com] [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Items | – Name: Title Label: Title Group: Ti Data: Septal LYVE1<superscript>+</superscript> macrophages control adipocyte stem cell adipogenic potential. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Yu%2C+Xiaotong%22">Yu, Xiaotong</searchLink><br /><searchLink fieldCode="AR" term="%22Hu%2C+Yanan%22">Hu, Yanan</searchLink><br /><searchLink fieldCode="AR" term="%22Lim%2C+Hwee+Ying%22">Lim, Hwee Ying</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Ziyi%22">Li, Ziyi</searchLink><br /><searchLink fieldCode="AR" term="%22Jaitin%2C+Diego+Adhemar%22">Jaitin, Diego Adhemar</searchLink><br /><searchLink fieldCode="AR" term="%22Yang%2C+Katharine%22">Yang, Katharine</searchLink><br /><searchLink fieldCode="AR" term="%22Kong%2C+Wan+Ting%22">Kong, Wan Ting</searchLink><br /><searchLink fieldCode="AR" term="%22Xu%2C+Jiaqian%22">Xu, Jiaqian</searchLink><br /><searchLink fieldCode="AR" term="%22Bejarano%2C+David+Alejandro%22">Bejarano, David Alejandro</searchLink><br /><searchLink fieldCode="AR" term="%22Bied%2C+Mathilde%22">Bied, Mathilde</searchLink><br /><searchLink fieldCode="AR" term="%22Orliaguet%2C+Lucie%22">Orliaguet, Lucie</searchLink><br /><searchLink fieldCode="AR" term="%22Rengasamy%2C+Gowshika%22">Rengasamy, Gowshika</searchLink><br /><searchLink fieldCode="AR" term="%22Chow%2C+Zachary%22">Chow, Zachary</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Christopher+Zhe+Wei%22">Lee, Christopher Zhe Wei</searchLink><br /><searchLink fieldCode="AR" term="%22Lum%2C+Josephine%22">Lum, Josephine</searchLink><br /><searchLink fieldCode="AR" term="%22Tian%2C+Jing%22">Tian, Jing</searchLink><br /><searchLink fieldCode="AR" term="%22Zhang%2C+Xiao-Meng%22">Zhang, Xiao-Meng</searchLink><br /><searchLink fieldCode="AR" term="%22Liu%2C+Honghao%22">Liu, Honghao</searchLink><br /><searchLink fieldCode="AR" term="%22Tan%2C+Shu+Wen%22">Tan, Shu Wen</searchLink><br /><searchLink fieldCode="AR" term="%22Chen%2C+Jinmiao%22">Chen, Jinmiao</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 8/28/2025, Vol. 389 Issue 6763, p1-19. 19p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Fat+cells%22">Fat cells</searchLink><br /><searchLink fieldCode="DE" term="%22Macrophages%22">Macrophages</searchLink><br /><searchLink fieldCode="DE" term="%22Phenotypes%22">Phenotypes</searchLink><br /><searchLink fieldCode="DE" term="%22Obesity%22">Obesity</searchLink><br /><searchLink fieldCode="DE" term="%22Transcriptomes%22">Transcriptomes</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Tissue macrophages reside in anatomically distinct subtissular niches that shape their identity and function. In white adipose tissue (WAT), we identified three macrophage populations with distinct localization, turnover, and phenotypes. Septal adipose tissue macrophages (sATMs), marked by CD209b and lymphatic vessel endothelial hyaluronan receptor 1, were long-lived and positioned in close proximity to adipocyte stem cells (ASCs) within the WAT septum. Within this shared niche, sATMs instructed the differentiation of ASCs into white adipocytes through transforming growth factor–β1 (TGFβ1). Depletion of sATMs, or the selective loss of TGFβ1 within tissue-resident macrophages, redirected ASC fate toward thermogenic adipocytes, enhancing WAT beiging and protecting against diet-induced obesity. These findings highlight the role of a discrete, anatomically defined macrophage population that governs ASC fate and orchestrates adipose tissue expansion. Editor's summary: In addition to their role in host defense, macrophages contribute to the development and remodeling of tissues. Yu et al. characterized macrophages found in the adipose tissue of mice on the basis of their gene expression, localization within the tissue, and developmental origin. A subset of macrophages localized in the same tissue microenvironment as adipocyte stem cells and promoted their differentiation into white adipocytes. Specific deletion of these macrophages promoted the differentiation of thermogenic, rather than white, adipocytes and prevented mice from becoming obese in response to a high-fat diet. A similar population of cells were identified in human adipose tissue. —Sarah H. Ross INTRODUCTION: Adipose tissue (AT) is a dynamic organ composed of lipid-storing adipocytes, adipocyte stem cells (ASCs), and resident immune cells. Macrophages are among the most abundant immune cells in AT and, depending on the physiological context, can maintain tissue function or drive inflammation. Prior studies have characterized inflammatory macrophages in obesity, but the identity and role of resident macrophages under steady state and their interaction with stromal populations is poorly understood. Recent evidence indicates that macrophage specialization may extend beyond tissue-level niches into more refined "subtissular" compartments. Whether such localization impacts AT macrophage identity and function has remained unresolved. RATIONALE: We hypothesized that subtissular macrophage niches within AT serve as instructive hubs for ASC fate specification. Using spatial, transcriptomic, and functional analyses in mice and humans, we investigated whether specific macrophage subsets localized to defined AT compartments, interacted with progenitor cells, and regulated adipogenesis. RESULTS: We defined three distinct AT macrophage (ATM) populations based on their subtissular localization and molecular signatures: parenchymal (pATMs), capsular (cATMs), and septal (sATMs). The sATMs, characterized by the expression of CD209b and LYVE1 (CD209b+LYVE1+), were selectively enriched in intralobular septa, a dense collagen- and hyaluronan-rich structure traversing adipocyte lobules, in close proximity to early CD26 expressing ASCs (ASCsCD26+). These sATMs were primarily embryonic-derived, long-lived, and distinct from monocyte-derived, inflammation-associated ATMs. In response to a high-fat diet (HFD) challenge, sATMs remained spatially restricted and resisted monocyte replacement whereas pATMs increased in number through both local proliferation and monocyte influx. Selective genetic depletion of sATMs using a Cd209b-driven DTR model enhanced thermogenesis, WAT beiging, increased oxygen consumption, and protection from HFD-induced obesity, independently of food intake. These mice also exhibited improved glucose tolerance and insulin sensitivity, along with reduced liver steatosis. Single-cell and bulk RNA-seq of AT stromal fractions identified ASCsCD26+ as highly proliferative, early progenitors localized in the septa. Upon sATM depletion, ASCCD26+ frequency declined, and their transcriptional profiles shifted toward a thermogenic, brown/beige fate. Ligand-receptor interaction modeling pinpointed TGFβ1 as a signal derived from sATMs that acted on ASCs via TGFβR1/2. Specific deletion of Tgfb1 in LYVE1+ or TIM4+ macrophages in vivo recapitulated sATM depletion phenotypes. In vitro, ASCsCD26+ from TGFβ1-deficient mice showed impaired white adipogenic differentiation and greater capacity for thermogenic conversion. We identified a conserved population of CD206+LYVE1+ human septal ATMs (hsATMs) in obese patients, expressing high levels of TGFB1 and residing adjacent to CD26+CD55+ early human ASCs (hASCsCD26+). Multiplex imaging confirmed close physical proximity between hsATMs and hASCsCD26+ within septal zones of human WAT. CONCLUSION: Subtissular localization may be a critical determinant of macrophage function and positions the adipose septum as a discrete immunometabolic niche essential for tissue remodeling. Our findings define a spatially confined niche containing resident macrophages and stem cells within the septum of white adipose tissue that governs adipose tissue plasticity and energy balance. Septal ATMs provided localized TGFβ1 signals that direct early adipocyte progenitors toward white adipocyte differentiation while restraining thermogenic potential. Depletion or functional inactivation of this sATM niche shifted the ASC fate toward beige adipogenesis, enhanced energy expenditure, and conferred systemic metabolic benefits in obesity. This regulatory axis between septal resident macrophages and adipocyte progenitors develops understanding of immune-stromal cross-talk in metabolic tissues. Targeting the sATM–TGFβ1–ASC axis may offer therapeutic strategies to boost WAT beiging and counteract obesity and insulin resistance without triggering inflammation. Spatially distinct macrophage niches govern adipogenesis.: White fat is organized into three anatomical compartments—septum, capsule, and parenchyma—each containing distinct populations of adipose tissue macrophages (ATMs). Septal macrophages (sATMs) are positioned in close contact with a population of early fat stem cells expressing CD26 (ASCsCD26+) within the septal niche. This spatial association enables sATMs to guide stem cell fate through TGFβ1 signaling, promoting the formation of energy-storing white fat cells. [Figure created using BioRender.com] [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.adg1128 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 19 StartPage: 1 Subjects: – SubjectFull: Fat cells Type: general – SubjectFull: Macrophages Type: general – SubjectFull: Phenotypes Type: general – SubjectFull: Obesity Type: general – SubjectFull: Transcriptomes Type: general Titles: – TitleFull: Septal LYVE1+ macrophages control adipocyte stem cell adipogenic potential. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Yu, Xiaotong – PersonEntity: Name: NameFull: Hu, Yanan – PersonEntity: Name: NameFull: Lim, Hwee Ying – PersonEntity: Name: NameFull: Li, Ziyi – PersonEntity: Name: NameFull: Jaitin, Diego Adhemar – PersonEntity: Name: NameFull: Yang, Katharine – PersonEntity: Name: NameFull: Kong, Wan Ting – PersonEntity: Name: NameFull: Xu, Jiaqian – PersonEntity: Name: NameFull: Bejarano, David Alejandro – PersonEntity: Name: NameFull: Bied, Mathilde – PersonEntity: Name: NameFull: Orliaguet, Lucie – PersonEntity: Name: NameFull: Rengasamy, Gowshika – PersonEntity: Name: NameFull: Chow, Zachary – PersonEntity: Name: NameFull: Lee, Christopher Zhe Wei – PersonEntity: Name: NameFull: Lum, Josephine – PersonEntity: Name: NameFull: Tian, Jing – PersonEntity: Name: NameFull: Zhang, Xiao-Meng – PersonEntity: Name: NameFull: Liu, Honghao – PersonEntity: Name: NameFull: Tan, Shu Wen – PersonEntity: Name: NameFull: Chen, Jinmiao IsPartOfRelationships: – BibEntity: Dates: – D: 28 M: 08 Text: 8/28/2025 Type: published Y: 2025 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 389 – Type: issue Value: 6763 Titles: – TitleFull: Science Type: main |
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