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Semaglutide ameliorates metabolic disorders in offspring via regulation of oocyte ROS of pre-pregnancy obesity mice

Acta Pharmacologica Sinica volume 46, pages 1664–1675 (2025)Cite this article

Abstract

Pre-pregnancy obesity (PPO) seriously threatens the health of both mother and offspring. Pre-pregnancy weight management is particularly important for the prevention of metabolic diseases in offspring. Semaglutide is one of the most effective glucagon-like peptide-1 agonizts for the management of obesity and metabolic diseases, but little is known about its effect on the long-term health of offspring. In this study we investigated the effects of semaglutide administered before pregnancy on the offspring health from PPO mice. PPO mice model was established by feeding with high-fat diet for 16 weeks, and then injected with semaglutide (30 nmol/kg-1·d-1, sc.) for 22 days before pregnancy. After the treatment, the mice were mated with normal males or underwent in vitro fertilization (IVF) for offspring reproduction. We showed that the semaglutide treatment not only improved the lipid and glucose metabolic disorders and fertility of PPO mice, but also significantly reversed the overweight, impaired energy balance, adipose inflammatory state, lipid and glucose metabolic disorders and insulin resistance of their IVF offspring. By conducting RNA-seq analysis, SOD activity and malondialdehyde assays in ovaries, as well as ROS staining in oocytes, we revealed that the semaglutide treatment reduced the elevated oxidative stress in ovaries and high ROS levels in oocytes from PPO mice, possibly through activating the PI3K/AKT pathway and improving the state of SOD. Interestingly, incubation of oocytes from semaglutide-treated dams with H2O2 (100 μM) in vitro during IVF blocked the protective effects of semaglultide against the metabolic disorders in the offspring. In conclusion, semaglutide treatment before pregnancy effectively alleviates obesity-related metabolic disorders in offspring. The regulation of ROS in oocytes plays a crucial role in the protective effects of semaglutide.

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Fig. 1: Effect of SEMA on body weight and energy balance in PPO dams.
Fig. 2: SEMA improves metabolism disorders as well as fertility in PPO dams.
Fig. 3: SEMA improves metabolism disorders in offspring from PPO dams.
Fig. 4: Ovarian RNA-sequencing reveals the downregulation of reactive oxygen species and upregulation of PI3K/AKT pathway after SEMA treatment.
Fig. 5: SEMA decreases the elevated oxidative stress through activating the PI3K/AKT pathway in ovaries from PPO dams.
Fig. 6: SEMA improves the adipose inflammatory state in offspring from PPO dams.
Fig. 7: Reversing anti-ROS effect of SEMA through H2O2 incubation reestablishes the metabolism disorders in offspring.
Fig. 8: Schema of the mechanism of this study.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81930008); National Key R&D Program of China (2022YFA1104500); National Institutes of Health, USA (5R01DK119652 and 1R01DK134574); Natural Science Foundation of Chongqing, China (cstc2021jcyj-msxmX0933).

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Author notes

  1. These authors contributed equally: Jun-kai Zhang, Xiao-ping Li, Yang Tang, Li-ping Zeng

Authors and Affiliations

  1. Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China

    Jun-kai Zhang, Xiao-ping Li, Yang Tang, Li-ping Zeng, Xuan Liu, Jian-li Zhang, Cai-yu Chen, Shuo Zheng, Xue Gong & Chun-yu Zeng

  2. Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, 400042, China

    Jun-kai Zhang, Xiao-ping Li, Yang Tang, Li-ping Zeng, Xuan Liu, Jian-li Zhang, Cai-yu Chen, Shuo Zheng, Xue Gong & Chun-yu Zeng

  3. Department of Cardiology, Sichuan Provincial Corps Hospital of Chinese People’s Armed Police Force (Sichuan Corps Hospital of PAP), Leshan, 614000, China

    Jun-kai Zhang

  4. Department of Cardiology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (the Second Affiliated Hospital of Hunan Normal University), Changsha, 410081, China

    Xiao-ping Li

  5. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Yang Tang

  6. Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China

    Li-ping Zeng & Chun-yu Zeng

  7. Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, China

    Zhi-zhao Liu

  8. Division of Renal Diseases & Hypertension, The George Washington University School of Medicine & Health Sciences, Washington, DC, USA

    Pedro A. Jose

  9. Endocrinology Department, The First Affiliated Hospital of The Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Li Guo

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Contributions

JKZ, LG and CYZ conceived and designed the study. JKZ, XPL, YT, LPZ, XL, JLZ, CYC and SZ performed the experiments. ZZL and XG participated in data analysis. JKZ and PAJ wrote the manuscript. LG and CYZ revised the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Li Guo or Chun-yu Zeng.

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Zhang, Jk., Li, Xp., Tang, Y. et al. Semaglutide ameliorates metabolic disorders in offspring via regulation of oocyte ROS of pre-pregnancy obesity mice. Acta Pharmacol Sin 46, 1664–1675 (2025). https://doi.org/10.1038/s41401-025-01501-1

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