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
Affiliations
Ya Zhang
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
Yang Cheng
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Jian Liu
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Jihui Zuo
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Liping Yan
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Ronald W. Thring
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Xueqing Ba
Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin, China
Dake Qi
College of Pharmacy, University of Manitoba, Winnipeg, Canada
Mingjiang Wu
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
Yitian Gao
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China; Corresponding author.
Haibin Tong
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China; Corresponding author.
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.
