Thermogenic Adipocytes Promote M2 Macrophage Polarization through CNNM4‐Mediated Mg Secretion
M2 macrophages promote adipose tissue thermogenesis which dissipates energy in the form of heat to combat obesity. However, the regulation of M2 macrophages by thermogenic adipocytes is unclear. Here, it is identified magnesium (Mg) as a thermogenic adipocyte-secreted factor to promote M2 macrophage polarization. Mg transporter Cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) induced by ADRB3-PKA-CREB signaling in thermogenic adipocytes during cold exposure mediates Mg efflux and Mg in turn binds to the DFG motif in mTOR to facilitate mTORC2 activation and M2 polarization in macrophages. In obesity, downregulation of CNNM4 expression inhibits Mg secretion from thermogenic adipocytes, which leads to decreased M2 macrophage polarization and thermogenesis. As a result, CNNM4 overexpression in adipocytes or Mg supplementation in adipose tissue ameliorates obesity by promoting thermogenesis. Importantly, an Mg wire implantation (AMI) approach is introduced to achieve adipose tissue-specific long-term Mg supplement. AMI promotes M2 macrophage polarization and thermogenesis and ameliorates obesity in mice. Taken together, a reciprocal regulation of thermogenic adipocytes and M2 macrophages important for thermogenesis is identified, and AMI is offered as a promising strategy against obesity.
Authors
- Xiaonong Zhang (ORCID: https://orcid.org/0000-0003-4133-5571)
- Anke Zhang (ORCID: https://orcid.org/0000-0002-0007-7724)
- Houshi Xu (ORCID: https://orcid.org/0000-0002-2878-0913)
- Zhen‐Ning Zhang (ORCID: https://orcid.org/0000-0003-3798-7104)
- Anwen Shao (ORCID: https://orcid.org/0000-0001-9986-6290)
- Junkun Jiang
- Sheng Chen (ORCID: https://orcid.org/0000-0002-5186-5069)
- Bing Luan (ORCID: https://orcid.org/0000-0002-0409-2964)
- Chaoyou Fang
- Yuqing Deng
- Wenhui Wang (ORCID: https://orcid.org/0000-0002-9623-0489)
- Chuan Zhang (ORCID: https://orcid.org/0000-0002-9311-0799)
- Jianmin Zhang (ORCID: https://orcid.org/0000-0003-4765-0812)
- Wenjing Yu
- Jiahua Ni (ORCID: https://orcid.org/0000-0003-4411-1899)
- Haonan Fan (ORCID: https://orcid.org/0009-0006-5681-788X)
- Ling Yuan (ORCID: https://orcid.org/0009-0002-0916-4696)
- Zibin Lu (ORCID: https://orcid.org/0000-0001-7174-9420)
- Huaming Li (ORCID: https://orcid.org/0000-0001-5661-6777)
- Xiaoyu Wang (ORCID: https://orcid.org/0009-0009-8943-131X)
Institutions
- Tongji University (CN)
- Allen Institute for Brain Science (US)
- Donghua University (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Suzhou Institute of Biomedical Engineering and Technology (CN)
- Zhejiang Lab (CN)
- Shanghai East Hospital (CN)
- Shanghai First People's Hospital (CN)
- Zhejiang Meteorological Bureau (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Huashan Hospital (CN)
- Tongji Hospital (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1002/advs.202401140
- Citations
- 5
- Primary Topic
- Magnesium in Health and Disease
- Type
- article
- Field-Weighted Citation Impact
- 1.55
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- National Key Research and Development Program of China