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Animal Models

BMAL1 deletion protects against obesity and non-alcoholic fatty liver disease induced by a high-fat diet

International Journal of Obesity volumeĀ 48,Ā pages 469ā€“476 (2024)Cite this article

Subjects

Abstract

Objectives

Obesity and non-alcoholic fatty liver disease (NAFLD) are major health concerns. The circadian rhythm is an autonomous and intrinsic timekeeping system closely associated with energy metabolism and obesity. Thus, this study explored the role of brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1), a circadian clock regulator, in the development of obesity and NAFLD.

Methods

We generated BMAL1 knockout (BMAL1 KO) mice to imitate circadian rhythm disruption. The study comprised three groups from the same litter: BMAL1 KO mice fed a high-fat diet (to establish obesity and NAFLD phenotypes), wild-type mice fed normal chow, and wild-type mice fed a high-fat diet. The metabolic and NAFLD phenotypes were assessed via physiological measurements and histological examinations. Quantitative polymerase chain reaction and western blotting were used to identify and validate changes in the signaling pathways responsible for the altered NAFLD phenotypes in the wild-type and BMAL1 KO mice.

Results

BMAL1 depletion protected against obesity and metabolic disorders induced by a high-fat diet. BMAL1 depletion also prevented hepatic steatosis and inhibited cluster of differentiation 36 and peroxisome proliferator-activated receptor gamma (i.e., PPARĪ³) expression.

Conclusions

BMAL1 plays an important role in the development of obesity and NAFLD and, thus, is a potential therapeutic target for these conditions.

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Fig. 1: Body weights and glucose metabolism biomarker levels in wild type (WT) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1) global knockout (BMAL1 KO) mice after 20 weeks of normal chow (NC) or a high-fat diet (HFD).
Fig. 2: Lipid metabolism phenotypes in wild-type (WT) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1) global knockout (BMAL1 KO) mice fed normal chow (NC) or a high-fat diet (HFD).
Fig. 3: Hepatic lipid metabolism phenotype in wild-type (WT) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1) global knockout (BMAL1 KO) mice fed normal chow (NC) or a high-fat diet (HFD).
Fig. 4: Liver lipid metabolism-related and nuclear receptor gene expression levels in wild-type (WT) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1) global knockout (BMAL1 KO) mice fed normal chow (NC) or a high-fat diet (HFD).

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Data availability

Data will be made available on request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant numbers 81800751, 81970458, and 82100882).

Author information

Author notes

  1. These authors contributed equally: Chongwen Zhan, Haoran Chen.

  2. These authors jointly supervised this work: Wenjuan Liu, Qiwei Shen.

Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital of Fudan University, Shanghai, China

    Chongwen Zhan,Ā Zhao Zhang,Ā Yikai Shao,Ā Bo Xu,Ā Rong Hua,Ā Qiyuan YaoĀ &Ā Qiwei Shen

  2. Department of Urology, Huashan Hospital of Fudan University, Shanghai, China

    Haoran Chen

  3. Department of Endocrinology, Huashan Hospital of Fudan University, Shanghai, China

    Wenjuan Liu

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  1. Chongwen Zhan
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Contributions

WL and QS conceived, designed, and supervised the study. CZ, HC, BX, YS, QY and RH conducted the study and analyzed the results. CZ and ZZ wrote and revised the manuscript. QS provided financial support.

Corresponding authors

Correspondence to Wenjuan Liu or Qiwei Shen.

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Zhan, C., Chen, H., Zhang, Z. et al. BMAL1 deletion protects against obesity and non-alcoholic fatty liver disease induced by a high-fat diet. Int J Obes 48, 469ā€“476 (2024). https://doi.org/10.1038/s41366-023-01435-w

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