Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation
Abstract Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immun...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62690-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235185058447360 |
|---|---|
| author | Yan Tao Jinhao Zang Tianci Wang Peixuan Song Zixin Zhou Huijie Li Yalin Wang Yiyang Liu Haipeng Jie Mei Kuang Hui Zhao Fuwu Wang Shen Dai Chun Guo Faliang Zhu Haiting Mao Fengming Liu Lining Zhang Qun Wang |
| author_facet | Yan Tao Jinhao Zang Tianci Wang Peixuan Song Zixin Zhou Huijie Li Yalin Wang Yiyang Liu Haipeng Jie Mei Kuang Hui Zhao Fuwu Wang Shen Dai Chun Guo Faliang Zhu Haiting Mao Fengming Liu Lining Zhang Qun Wang |
| author_sort | Yan Tao |
| collection | DOAJ |
| description | Abstract Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+ overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases. |
| format | Article |
| id | doaj-art-e3c4f7ed9f1340edac2171df95430dca |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e3c4f7ed9f1340edac2171df95430dca2025-08-20T04:02:54ZengNature PortfolioNature Communications2041-17232025-08-0116112010.1038/s41467-025-62690-1Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentationYan Tao0Jinhao Zang1Tianci Wang2Peixuan Song3Zixin Zhou4Huijie Li5Yalin Wang6Yiyang Liu7Haipeng Jie8Mei Kuang9Hui Zhao10Fuwu Wang11Shen Dai12Chun Guo13Faliang Zhu14Haiting Mao15Fengming Liu16Lining Zhang17Qun Wang18Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Statistics, Columbia UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityKey Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Physiology and Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityKey Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong UniversityAbstract Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+ overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases.https://doi.org/10.1038/s41467-025-62690-1 |
| spellingShingle | Yan Tao Jinhao Zang Tianci Wang Peixuan Song Zixin Zhou Huijie Li Yalin Wang Yiyang Liu Haipeng Jie Mei Kuang Hui Zhao Fuwu Wang Shen Dai Chun Guo Faliang Zhu Haiting Mao Fengming Liu Lining Zhang Qun Wang Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation Nature Communications |
| title | Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| title_full | Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| title_fullStr | Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| title_full_unstemmed | Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| title_short | Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| title_sort | obesity associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation |
| url | https://doi.org/10.1038/s41467-025-62690-1 |
| work_keys_str_mv | AT yantao obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT jinhaozang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT tianciwang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT peixuansong obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT zixinzhou obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT huijieli obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT yalinwang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT yiyangliu obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT haipengjie obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT meikuang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT huizhao obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT fuwuwang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT shendai obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT chunguo obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT faliangzhu obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT haitingmao obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT fengmingliu obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT liningzhang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation AT qunwang obesityassociatedmacrophagesdictateadiposestemcellferroptosisandvisceralfatdysfunctionbypropagatingmitochondrialfragmentation |