2. Academic Validation
  3. Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity

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

  • Signal Transduct Target Ther. 2024 Aug 23;9(1):218. doi: 10.1038/s41392-024-01930-0.
Lu Fang # 1,  Changjie Liu # 2,  Zong-Zhe Jiang 3 4,  Mengxiao Wang 1,  Kang Geng 4 5,  Yangkai Xu 1,  Yujie Zhu 1,  Yiwen Fu 1,  Jing Xue 6,  Wenxin Shan 1,  Qi Zhang 1,  Jie Chen 1,  Jiahong Chen 1,  Mingming Zhao 7,  Yuxuan Guo 1,  K W Michael Siu 8 9,  Y Eugene Chen 10,  Yong Xu 11 12,  Donghui Liu 13,  Lemin Zheng 14 15
Affiliations

Affiliations

  • 1 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 100191, Beijing, China.
  • 2 Department of Blood Transfusion, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510000, Guangdong, China.
  • 3 Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China.
  • 4 Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China.
  • 5 Department of plastic and burns surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China.
  • 6 Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, 100050, Beijing, China.
  • 7 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research; Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, 100191, Beijing, China.
  • 8 Center for Mass Spectrometry Research and Clinical Application, Shandong Public Health Clinical Center Affiliated to Shandong University, Lishan Campus, 46 Lishan Road, Jinan, Shandong, China.
  • 9 Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada.
  • 10 Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.
  • 11 Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China. xywyll@aliyun.com.
  • 12 Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, China. xywyll@aliyun.com.
  • 13 Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510000, China. eyliudh@scut.edu.cn.
  • 14 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 100191, Beijing, China. zhengl@bjmu.edu.cn.
  • 15 Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, 100050, Beijing, China. zhengl@bjmu.edu.cn.
  • # Contributed equally.
PMID: 39174522 DOI: 10.1038/s41392-024-01930-0
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.

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