Tauroursodeoxycholic acid functions as a critical effector mediating insulin sensitization of metformin in obese mice

Ya Zhang; Yang Cheng; Jian Liu; Jihui Zuo; Liping Yan; Ronald W Thring; Xueqing Ba; Dake Qi; Mingjiang Wu; Yitian Gao; Haibin Tong

doi:10.1016/j.redox.2022.102481

Tauroursodeoxycholic acid functions as a critical effector mediating insulin sensitization of metformin in obese mice

Redox Biol. 2022 Nov:57:102481. doi: 10.1016/j.redox.2022.102481. Epub 2022 Sep 15.

Authors

Ya Zhang¹, Yang Cheng², Jian Liu², Jihui Zuo², Liping Yan², Ronald W Thring², Xueqing Ba³, Dake Qi⁴, Mingjiang Wu², Yitian Gao⁵, Haibin Tong⁶

Affiliations

¹ Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China; Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
² Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China.
³ Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin, China.
⁴ College of Pharmacy, University of Manitoba, Winnipeg, Canada.
⁵ Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China. Electronic address: gyt@wzu.edu.cn.
⁶ Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China. Electronic address: tonghaibin@gmail.com.

Abstract

Metformin is widely used to surmount insulin resistance (IR) and type 2 diabetes. Accumulating evidence suggests that metformin may improve IR through regulating gut microbiota and bile acids. However, the underlying mechanisms remain unclear. Our metabolomic analysis showed that metformin significantly increased the accumulation of tauroursodeoxycholic acid (TUDCA) in intestine and liver from high-fat diet (HFD)-induced IR mice. TUDCA also alleviated IR, and reduced oxidative stress and intestinal inflammation in ob/ob mice. TUDCA blocked KEAP1 to bind with Nrf2, resulting in Nrf2 translocation into nuclear and initiating the transcription of antioxidant genes, which eventually reduced intracellular ROS accumulation and improved insulin signaling. Analysis of gut microbiota further revealed that metformin reduced the relative abundance of Bifidobacterium, which produces bile salt hydrolase (BSH). The reduction in BSH was probably crucial for the accumulation of TUDCA. Metformin also increased the proportion of Akkermanisia muciniphlia in gut microbiota of ob/ob mice via TUDCA. These beneficial effects of metformin in remodeling gut microbiota, reducing oxidative stress and improving insulin sensitivity were partly due to the accumulation of TUDCA, suggesting that TUDCA may be a potential therapy for metabolic syndrome.

Keywords: Bile salt hydrolase; Insulin resistance; Metformin; Nrf2; Tauroursodeoxycholic acid.