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Theranostics 2023; 13(9):3103-3116. doi:10.7150/thno.81893 This issue Cite

Research Paper

Vertical sleeve gastrectomy-derived gut metabolite licoricidin activates beige fat thermogenesis to combat obesity

Zhangliu Jin^1*, Wen Meng^2*, Ting Xiao^2,3, Jiangming Deng², Jing Wang², Jie Wen², Kai Chen¹, Liwen Wang², Juanhong Liu², Qingxin Li², Jieyu He², Zheng Wang⁴, Wei Liu^1✉, Feng Liu^2✉

1. Department of General Surgery, Division of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
2. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
3. Department of Hepatology, Hunan Children's Hospital, Changsha 410000, Hunan, China.
4. College of Bioscience & Biotechnology of Hunan Agricultural University, Changsha 410128, Hunan, China.
* These authors have contributed equally to the work.

✉ Corresponding authors: Dr. Feng Liu, liuf001edu.cn; Dr. Wei Liu, liuweixyedu.cn.

Abstract

Obesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement.

Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites.

Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice.

Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.

Keywords: Vertical sleeve gastrectomy, Gut metabolite, Licoricidin, Obesity, Thermogenesis

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