Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity

Hu Hua; Yue Zhang; Fei Zhao; Ke Chen; Tong Wu; Qianqi Liu; Songming Huang; Aihua Zhang; Zhanjun Jia

doi:10.1016/j.isci.2021.102077

Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity

iScience. 2021 Jan 20;24(2):102077. doi: 10.1016/j.isci.2021.102077. eCollection 2021 Feb 19.

Authors

Hu Hua^{1

2

3}, Yue Zhang^{1

2

3}, Fei Zhao², Ke Chen^{4

5}, Tong Wu^{4

5}, Qianqi Liu^{4

5}, Songming Huang^{1

2

3}, Aihua Zhang^{1

2

3}, Zhanjun Jia^{1

2

3}

Affiliations

¹ Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, P. R. of China.
² Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, P. R. of China.
³ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, P. R. of China.
⁴ Department of Endocrinology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, China.
⁵ Department of Child Health Care, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, China.

Abstract

Celastrol, a compound extracted from traditional Chinese medicine, has been reported as a potent anti-obesity agent with controversial mechanisms. Here both C57BL/6J and leptin-deficient (ob/ob) mice fed a high-fat diet (HFD) displayed body weight loss after celastrol therapy, opposing the previous viewpoint that celastrol improves obesity by sensitizing leptin signaling. More importantly, celastrol downregulated lipid transporters in the intestine, increased lipid excretion in feces, and reduced body weight gain in HFD mice. Meanwhile, analysis of gut microbiota revealed that celastrol altered the gut microbiota composition in HFD-fed mice, and modulating gut microbiota by antibiotics or fecal microbiota transplantation blocked the celastrol effect on intestinal lipid transport and body weight gain, suggesting a critical role of the gut microbiota composition in mediating the anti-obesity role of celastrol under HFD. Together, the findings revealed that celastrol reduces intestinal lipid absorption to antagonize obesity by resetting the gut microbiota profile under HFD feeding.

Keywords: Biological Sciences; Endocrinology; Microbiology; Microbiome Physiology.