FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology

Lexiang Yu¹, Yong Xiao Yang², Zhen Gong³, Qianfen Wan⁴, Yifei Du⁵, Qiuzhong Zhou⁶, Yang Xiao⁷, Tarik Zahr⁴, Zhaobin Wang⁸, Zhewei Yu⁹, Kangkang Yang¹⁰, Jinyang Geng¹⁰, Susan K Fried¹¹, Jing Li¹², Rebecca A Haeusler⁴, Kam W Leong⁷, Lin Bai⁸, Yingjie Wu¹⁰, Lei Sun⁶, Pan Wang², Bao Ting Zhu², Liheng Wang¹³, Li Qiang¹⁴

Affiliations

¹ Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
² Research Center for Endocrine and Metabolic Diseases, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
³ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁴ Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
⁵ MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
⁶ Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
⁷ Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.
⁸ Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
⁹ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
¹⁰ Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital, School of Laboratory Animal & Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250021, China; Institute for Genome Engineered Animal Models of Human Diseases, College of Integrative Medicine, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian 116044, China.
¹¹ Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
¹³ Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: lihengwang@hsc.pku.edu.cn.
¹⁴ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: qiang@pku.edu.cn.

PMID: 39674176
PMCID: PMC11885036 (available on 2026-03-04)
DOI: 10.1016/j.cmet.2024.11.001

FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology

Lexiang Yu et al. Cell Metab. 2025.

. 2025 Mar 4;37(3):656-672.e7.

doi: 10.1016/j.cmet.2024.11.001. Epub 2024 Dec 13.

Authors

Affiliations

¹ Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
² Research Center for Endocrine and Metabolic Diseases, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
³ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁴ Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
⁵ MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
⁶ Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
⁷ Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.
⁸ Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
⁹ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
¹⁰ Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital, School of Laboratory Animal & Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250021, China; Institute for Genome Engineered Animal Models of Human Diseases, College of Integrative Medicine, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian 116044, China.
¹¹ Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
¹³ Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: lihengwang@hsc.pku.edu.cn.
¹⁴ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: qiang@pku.edu.cn.

PMID: 39674176
PMCID: PMC11885036 (available on 2026-03-04)
DOI: 10.1016/j.cmet.2024.11.001

Abstract

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Keywords: FcRn; IgG; adipose tissue remodeling; insulin receptor; insulin resistance; obesity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology

Affiliations

FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases