Department of General Surgery, Division of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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.
Theranostics. 2023 May 21;13(9):3103-3116. doi: 10.7150/thno.81893. eCollection 2023.
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. 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. 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. 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.
肥胖是一种慢性代谢性疾病，影响着全世界的个体。减重手术，如垂直袖状胃切除术（VSG），为肥胖小鼠和人类提供了持续的体重减轻和改善葡萄糖稳态的效果。然而，确切的潜在机制仍难以捉摸。在这项研究中，我们研究了肠道代谢物在 VSG 诱导的抗肥胖作用和代谢改善中的潜在作用和作用机制。高脂肪饮食（HFD）喂养的 C57BL/6J 小鼠接受了 VSG 手术。使用代谢笼实验监测小鼠的能量消耗。通过 16S rRNA 测序和代谢组学分别确定 VSG 对肠道微生物群和代谢物的影响。通过对代谢物的口服给药和脂肪垫注射，在小鼠中检查了鉴定出的肠道代谢物的代谢有益作用。VSG 在小鼠中极大地增加了米色脂肪中的产热基因表达，这与能量消耗的增加有关。VSG 重塑了肠道微生物群组成，导致包括甘草素在内的肠道代谢物水平升高。甘草素通过激活 Adrb3-cAMP-PKA 信号通路促进米色脂肪中的产热基因表达，导致 HFD 喂养小鼠体重增加减少。我们确定了甘草素，它介导了小鼠肠道和脂肪组织之间的串扰，作为 VSG 引发的抗肥胖代谢物。鉴定出的抗肥胖小分子应为肥胖及其相关代谢性疾病的治疗选择提供新的见解。
