Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice.
Vertical sleeve gastrectomy (VSG) is one of the most commonly performed clinical bariatric surgeries used for the remission of obesity and diabetes. However, the precise molecular mechanism by which VSG exerts its beneficial effects remains elusive. We report that the membrane-bound G protein-coupled bile acid receptor, GPBAR-1 (also known as TGR5), is required to mediate the effects of anti-obesity, anti-hyperglycemia, and improvements of fatty liver of VSG in mice. In the absence of TGR5, the beneficial metabolic effects of VSG in mice are lost. Moreover, we found that the expression of TGR5 increased significantly after VSG, and VSG alters both BA levels and composition in mice, resulting in enhancement of TGR5 signaling in the ileum and brown adipose tissues, concomitant with improved glucose control and increased energy expenditure.



Our study elucidates a novel underlying mechanism by which VSG achieves its postoperative therapeutic effects through enhanced TGR5 signaling. (Hepatology 2016;64:760-773).
Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Lili
L
Ding
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.|Department of Pharmaceutical Sciences, West Coast University, School of Pharmacy, Los Angeles, CA.
Kyle M
KM
Sousa
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.|State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian.
Lihua
L
Jin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
Bingning
B
Dong
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Byung-Wook
BW
Kim
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Ricardo
R
Ramirez
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Zhenzhou
Z
Xiao
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Ying
Y
Gu
Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Qiaoling
Q
Yang
Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Jie
J
Wang
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.
Donna
D
Yu
University of California, Irvine School of Medicine, Orange, CA.
Alessio
A
Pigazzi
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.|Department of Pharmaceutical Sciences, West Coast University, School of Pharmacy, Los Angeles, CA.
Dustin
D
Schones
Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Li
L
Yang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
David
D
Moore
Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Zhengtao
Z
Wang
Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA.|Graduate School of Biological Science, City of Hope National Medical Center, Duarte, CA.
Wendong
W
Huang
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D004734:Energy Metabolism; D005234:Fatty Liver / Q000601:surgery; D005743:Gastrectomy; D007082:Ileum / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss
D001647:Bile Acids and Salts; C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled