Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity

Xiaojing Jia¹, Hong Lin¹, Yilan Ding¹, Chunyan Hu¹, Shuangyuan Wang¹, Mian Li¹, Yu Xu¹, Min Xu¹, Feiyue Huang¹, Feixia Shen², Xuejiang Gu², Yiming Mu³, Lulu Chen⁴, Tianshu Zeng⁴, Lixin Shi⁵, Qing Su⁶, Xuefeng Yu⁷, Li Yan⁸, Guijun Qin⁹, Qin Wan¹⁰, Gang Chen¹¹, Xulei Tang¹², Zhengnan Gao¹³, Ruying Hu¹⁴, Zuojie Luo¹⁵, Yingfen Qin¹⁵, Li Chen¹⁶, Xinguo Hou¹⁶, Yanan Huo¹⁷, Qiang Li¹⁸, Guixia Wang¹⁹, Yinfei Zhang²⁰, Chao Liu²¹, Youmin Wang²², Shengli Wu²³, Yujin Zhu²³, Tao Yang²⁴, Huacong Deng²⁵, Jiajun Zhao²⁶, Yifang Zhang²⁷, Xingkun Xu¹, Huapeng Wei¹, Jie Zheng¹, Tiange Wang¹, Zhiyun Zhao¹, Guang Ning¹, Yuhong Chen¹, Weiqing Wang²⁸, Yufang Bi²⁹, Jieli Lu³⁰

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
² The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Chinese People's Liberation Army General Hospital, Beijing, China.
⁴ Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Affiliated Hospital of Guiyang Medical College, Guiyang, China.
⁶ Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁹ The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹⁰ The Affiliated Hospital of Southwest Medical University, Luzhou, China.
¹¹ Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
¹² The First Hospital of Lanzhou University, Lanzhou, China.
¹³ Dalian Municipal Central Hospital, Dalian, China.
¹⁴ Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
¹⁵ The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
¹⁶ Qilu Hospital of Shandong University, Jinan, China.
¹⁷ Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.
¹⁸ The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
¹⁹ The First Hospital of Jilin University, Changchun, China.
²⁰ Central Hospital of Shanghai Jiading District, Shanghai, China.
²¹ Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China.
²² The First Affiliated Hospital of Anhui Medical University, Hefei, China.
²³ Karamay Municipal People's Hospital, Xinjiang, China.
²⁴ The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
²⁵ The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
²⁶ Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
²⁷ Center for High Performance Computing, Shanghai Jiao Tong University, Shanghai, China.
²⁸ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: wqingw61@shsmu.edu.cn.
²⁹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: byf10784@rjh.com.cn.
³⁰ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: ljl11319@rjh.com.cn.

PMID: 41005299
DOI: 10.1016/j.xcrm.2025.102372

Free article

Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity

Xiaojing Jia et al. Cell Rep Med. 2025.

Free article

. 2025 Nov 18;6(11):102372.

doi: 10.1016/j.xcrm.2025.102372. Epub 2025 Sep 25.

Authors

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
² The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Chinese People's Liberation Army General Hospital, Beijing, China.
⁴ Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Affiliated Hospital of Guiyang Medical College, Guiyang, China.
⁶ Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁹ The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹⁰ The Affiliated Hospital of Southwest Medical University, Luzhou, China.
¹¹ Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
¹² The First Hospital of Lanzhou University, Lanzhou, China.
¹³ Dalian Municipal Central Hospital, Dalian, China.
¹⁴ Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
¹⁵ The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
¹⁶ Qilu Hospital of Shandong University, Jinan, China.
¹⁷ Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.
¹⁸ The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
¹⁹ The First Hospital of Jilin University, Changchun, China.
²⁰ Central Hospital of Shanghai Jiading District, Shanghai, China.
²¹ Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China.
²² The First Affiliated Hospital of Anhui Medical University, Hefei, China.
²³ Karamay Municipal People's Hospital, Xinjiang, China.
²⁴ The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
²⁵ The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
²⁶ Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
²⁷ Center for High Performance Computing, Shanghai Jiao Tong University, Shanghai, China.
²⁸ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: wqingw61@shsmu.edu.cn.
²⁹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: byf10784@rjh.com.cn.
³⁰ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: ljl11319@rjh.com.cn.

PMID: 41005299
DOI: 10.1016/j.xcrm.2025.102372

Abstract

Obesity, a major public health challenge, is characterized by substantial phenotypic heterogeneity. Here, we employ the discriminative dimensionality reduction tree (DDRTree) method to routine clinical data from 18,733 Chinese individuals with obesity enrolled in the nationwide China Cardiometabolic Disease and Cancer Cohort (4C) study. We identify five distinct metabolic phenotypes, among which the phenotype characterized by hyperglycemia and insulin resistance exhibits a higher risk of glycemic deterioration, while the phenotype characterized by hypertension and dyslipidemia demonstrates an elevated risk of microvascular and macrovascular diseases. These findings are validated in an independent prospective cohort. Additionally, we reveal distinctive metabolomic features that contribute to the heterogeneity of obesity in the 4C study. To translate our findings into practice, we develop a user-friendly online tool to assess event risks in the obese population. Overall, our analysis illustrates the underlying phenotypic variations influencing subsequent obesity-related outcomes, emphasizing the importance of precision medicine in obesity management.

Keywords: DDRTree; cardiovascular disease; diabetes; heterogeneity; obesity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity

Affiliations

Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

Full Text Sources