Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2024-08-23
DOI
https://doi.org/10.1038/s41392-024-01930-0
Citations
13
Primary Topic
S100 Proteins and Annexins
Type
article
Field-Weighted Citation Impact
3.04

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article

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity

Y. Eugene Chen, Kin Wai Michael Siu, Kang Geng, Changjie Liu et al.
13 citations
Signal Transduction and Targeted Therapy
S100 Proteins and Annexins
3.04
article

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity

Y. Eugene Chen, Kin Wai Michael Siu, Kang Geng, Changjie Liu, Jiahong Chen, Yiwen Fu, Yuxuan Guo, Yangkai Xu, Zongzhe Jiang, Yujie Zhu, Qi Zhang, Donghui Liu, Mengxiao Wang, Lu Fang, Lemin Zheng, Mingming Zhao, Jing Xue, Jie Chen, Wenxin Shan, Yong Xu
article en
13 citations

Abstract

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.

Signal Transduction and Targeted TherapyVol. 9(1)
King University (US), Shandong University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), University of Michigan (US), Affiliated Hospital of Southwest Medical University (CN), Beijing Tian Tan Hospital (CN), First Affiliated Hospital of Sichuan Medical University (CN), Guangzhou First People's Hospital (CN), Peking University Third Hospital (CN), University of Windsor (CA), South China University of Technology (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, Peking University, Guangzhou Municipal Science and Technology Project
Good health and well-being
Openalex Percentile: Top 8%
S100 Proteins and Annexins
3.04
DOIOpen Access PDFOpenAlex
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