EBioMedicine (Jul 2025)

GDF15 and its receptors as pathways mediating smoking related weight changeResearch in context

  • Alexander C. Tinworth,
  • Andri Iona,
  • Pang Yao,
  • Iona Y. Millwood,
  • Hannah Fry,
  • Jonathan Clarke,
  • Baihan Wang,
  • Mohsen Mazidi,
  • Christiana Kartsonaki,
  • Robin G. Walters,
  • Huaidong Du,
  • Canqing Yu,
  • Yiping Chen,
  • Dianjianyi Sun,
  • Ling Yang,
  • Dan Valle Schmidt,
  • Jun Lv,
  • Daniel Avery,
  • Liming Li,
  • Derrick A. Bennett,
  • Richard Peto,
  • Robert Clarke,
  • Fiona Bragg,
  • Zhengming Chen,
  • Junshi Chen,
  • Zhengming Chen,
  • Robert Clarke,
  • Rory Collins,
  • Liming Li,
  • Jun Lv,
  • Richard Peto,
  • Robin Walters,
  • Daniel Avery,
  • Maxim Bernard,
  • Derrick Bennett,
  • Ruth Boxall,
  • Ka Hung Chan,
  • Yiping Chen,
  • Charlotte Clarke,
  • Jonathan Clarke,
  • Huaidong Du,
  • Ahmed Edris Mohamed,
  • Hannah Fry,
  • Simon Gilbert,
  • Pek Kei Im,
  • Andri Iona,
  • Maria Kakkoura,
  • Christiana Kartsonaki,
  • Hubert Lam,
  • Kuang Lin,
  • James Liu,
  • Mohsen Mazidi,
  • Iona Millwood,
  • Sam Morris,
  • Qunhua Nie,
  • Alfred Pozarickij,
  • Maryam Rahmati,
  • Paul Ryder,
  • Dan Schmidt,
  • Becky Stevens,
  • Iain Turnbull,
  • Baihan Wang,
  • Lin Wang,
  • Neil Wright,
  • Ling Yang,
  • Xiaoming Yang,
  • Pang Yao,
  • Xiao Han,
  • Can Hou,
  • Qingmei Xia,
  • Chao Liu,
  • Pei Pei,
  • Dianjanyi Sun,
  • Canqing Yu,
  • Lang Pan,
  • Zengchang Pang,
  • Ruqin Gao,
  • Shanpeng Li,
  • Haiping Duan,
  • Shaojie Wang,
  • Yongmei Liu,
  • Ranran Du,
  • Yajing Zang,
  • Liang Cheng,
  • Xiaocao Tian,
  • Hua Zhang,
  • Yaoming Zhai,
  • Feng Ning,
  • Xiaohui Sun,
  • Feifei Li,
  • Silu Lv,
  • Junzheng Wang,
  • Wei Hou,
  • Wei Sun,
  • Shichun Yan,
  • Xiaoming Cui,
  • Chi Wang,
  • Zhenyuan Wu,
  • Yanjie Li,
  • Quan Kang,
  • Huiming Luo,
  • Tingting Ou,
  • Xiangyang Zheng,
  • Zhendong Guo,
  • Shukuan Wu,
  • Yilei Li,
  • Huimei Li,
  • Ming Wu,
  • Yonglin Zhou,
  • Jinyi Zhou,
  • Ran Tao,
  • Jie Yang,
  • Jian Su,
  • Fang Liu,
  • Jun Zhang,
  • Yihe Hu,
  • Yan Lu,
  • Liangcai Ma,
  • Aiyu Tang,
  • Shuo Zhang,
  • Jianrong Jin,
  • Jiangchao Liu,
  • Mei Lin,
  • Zhenzhen Lu,
  • Lifang Zhou,
  • Changping Xie,
  • Jian Lan,
  • Tingping Zhu,
  • Yun Liu,
  • Liuping Wei,
  • Liyuan Zhou,
  • Ningyu Chen,
  • Yulu Qin,
  • Sisi Wang,
  • Xianping Wu,
  • Ningmei Zhang,
  • Xiaofang Chen,
  • Xiaoyu Chang,
  • Mingqiang Yuan,
  • Xia Wu,
  • Xiaofang Chen,
  • Wei Jiang,
  • Jiaqiu Liu,
  • Qiang Sun,
  • Faqing Chen,
  • Xiaolan Ren,
  • Caixia Dong,
  • Hui Zhang,
  • Enke Mao,
  • Xiaoping Wang,
  • Tao Wang,
  • Xi Zhang,
  • Kai Kang,
  • Shixian Feng,
  • Huizi Tian,
  • Lei Fan,
  • XiaoLin Li,
  • Huarong Sun,
  • Pan He,
  • Xukui Zhang,
  • Min Yu,
  • Ruying Hu,
  • Hao Wang,
  • Xiaoyi Zhang,
  • Yuan Cao,
  • Kaixu Xie,
  • Lingli Chen,
  • Dun Shen,
  • Xiaojun Li,
  • Donghui Jin,
  • Li Yin,
  • Huilin Liu,
  • Zhongxi Fu,
  • Xin Xu,
  • Hao Zhang,
  • Jianwei Chen,
  • Yuan Peng,
  • Libo Zhang,
  • Chan Qu

DOI
https://doi.org/10.1016/j.ebiom.2025.105806
Journal volume & issue
Vol. 117
p. 105806

Abstract

Read online

Summary: Background: Smokers have lower body weight than non-smokers, while smoking cessation results in weight gain. Understanding the mechanisms involved can help identify potential therapeutic targets to enhance smoking cessation. Methods: We measured plasma levels of growth/differentiation factor 15 (GDF15), a stress-responsive protein, and its two receptors (proto-oncogene tyrosine-protein kinase receptor Ret [RET], GDNF family receptor alpha-like [GFRAL]) among 3936 Chinese adults (mean BMI 24.0 kg/m2), using Olink and SomaScan platforms. We assessed associations of individual proteins and GDF15/receptor ratios with smoking and adiposity using linear regression. In two-sample Mendelian randomization (MR) analyses, we used genetic variants for smoking intensity from publicly available GWAS as instruments to assess their causal associations with adiposity and plasma levels of proteins in East Asian and European populations. We further assessed the effects of GDF15 and GDF15/receptor ratios in mediating smoking-related weight change. Findings: Overall, smokers had significantly lower BMI (23.1 [0.2] kg/m2) than never-smokers (24.0 [0.1] kg/m2), while former smokers had the highest levels of BMI (24.6 [0.2] kg/m2) and other measures of adiposity (e.g., waist circumference, waist/hip ratio, and body fat percentage). In observational analyses, smoking was positively associated with GDF15 and with GDF15/receptor ratios from both platforms, with GDF15 levels increasing steeply with number of cigarettes smoked on the assessment day. In MR analyses, smoking intensity was significantly associated with a reduced BMI in East Asians and with higher GDF15 levels in both East Asian and European populations. SomaScan_GDF15 partially mediated the associations of smoking with all adiposity measures, while Olink_GDF15 mediated the association with body fat percentage. The GDF15/RET ratio more robustly mediated the smoking-adiposity relationships than GDF15 alone in both platforms. Interpretation: In Chinese adults GDF15 plays a role in mediating smoking-related weight change, and could serve as a therapeutic target to facilitate smoking cessation and minimise cessation-induced weight gain. Funding: British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.

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