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Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in ob/ob mice

International Journal of Obesity volume 44, pages 937–947 (2020)Cite this article

Subjects

Abstract

Objective

Ectopic lipid deposition is closely associated with type 2 diabetes (T2D). Accumulating evidence shows that GLP-1 receptor agonists (GLP-1 RAs) improve obesity and liver steatosis. However, it remains unknown whether and how they ameliorate lipid deposition in skeletal muscle. This study aimed to investigate the effect of exenatide (a GLP-1 RA) on intramyocellular lipid deposition in the skeletal muscle of T2D models and its dependence on weight loss.

Methods

Ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide (24 nmol/kg), leptin (1 mg/kg), or saline control intraperitoneally once daily for 4 weeks. Phenotypic evaluations were performed during and after the intervention. PA-induced myoblast C2C12 cells were used as an in vitro model. The expression of key enzymes involved in lipid metabolism was assessed in the skeletal muscle of ob/ob mice and DIO mice.

Results

In ob/ob mice, 4-week exenatide treatment did not improve the body weight and fat mass, but modestly ameliorated intramyocellular lipid deposition and lipid profiles. In DIO mice, it remarkably alleviated the body weight, lipid profiles, and intramyocellular lipid deposition. In the skeletal muscle of these two models, exenatide treatment activated the AMP-activated protein kinase (AMPK) signaling pathway, stimulated lipid oxidation enzymes, and upregulated the insulin signaling pathway. In vitro, exendin-4 activated the AMPK signaling pathway and stimulated lipid metabolism to improve lipid accumulation in palmitate-induced myoblast C2C12 cells.

Conclusions

Exenatide ameliorated intramyocellular lipid deposition without body weight reduction in ob/ob mice, but alleviated body weight and intramyocellular lipid deposition in DIO mice. The underlying mechanism included the activation of AMPK signaling pathway and improvement in insulin sensitivity, independent of weight loss in ob/ob mice.

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Fig. 1: Four-week exenatide treatment did not reduce body weight but improved glucose and insulin tolerance of ob/ob mice.
Fig. 2: Four-week exenatide treatment reduced body weight and improved lipid profiles and glucose tolerance in DIO mice.
Fig. 3: Exenatide ameliorated intramyocellular lipid deposition in ob/ob mice and DIO mice.
Fig. 4: Exenatide stimulated the AMPK signaling pathway and improved lipid metabolism and insulin sensitivity in the skeletal muscle of ob/ob mice.
Fig. 5: Exenatide activated the AMPK signaling and improved lipid metabolism and insulin sensitivity in the skeletal muscle of DIO mice.
Fig. 6: Exendin-4 improved lipid deposition and insulin sensitivity by activating the AMPK signaling pathway in PA-treated C2C12 myotube cells.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China Grant (81670782 and 81970741 FX), the Guangdong High-Level Talents Special Support Program (2016TQ03R590 FX), the Local Innovative and Research Teams Projects of Guangdong Pearl River Talents Program (2017BT 01S131 to JW and FX), the Pearl River S&T Nova Program of Guangzhou (201610010175 FX), and the NSFC-CIHR (81261120565 JW). FX was the guarantor of this study, had full access to all the data in the study, and took responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Fen Xu, Huanyi Cao, Zonglan Chen, Huimin Gu, Wanrong Guo, Beisi Lin & Jianping Weng

  2. Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China

    Fen Xu, Huanyi Cao, Zonglan Chen, Wanrong Guo, Beisi Lin & Jianping Weng

  3. Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China

    Huimin Gu

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  1. Fen Xu
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Contributions

FX contributed to the study design, acquisition of data, data interpretation, manuscript writing and revision. HC researched data, performed animal studies and cell culture, and analyzed data and revised the manuscript. ZC researched data, performed animal studies and analyzed data. HG contributed to the study design and data analysis. WG contributed to data analysis and manuscript revision. BL contributed to animal studies. JW contributed to the study design, data analysis, revision of the manuscript, and approval of the version to be submitted.

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Correspondence to Jianping Weng.

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Xu, F., Cao, H., Chen, Z. et al. Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in ob/ob mice. Int J Obes 44, 937–947 (2020). https://doi.org/10.1038/s41366-019-0513-y

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