title: Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice.
abstract: The metabolic benefits induced by gastric bypass, currently the most effective treatment for morbid obesity, are associated with bile acid (BA) delivery to the distal intestine. However, mechanistic insights into BA signaling in the mediation of metabolic benefits remain an area of study. The bile diversion () mouse model, in which the gallbladder is anastomosed to the distal jejunum, was used to test the specific role of BA in the regulation of glucose and lipid homeostasis. Metabolic phenotype, including body weight and composition, glucose tolerance, energy expenditure, thermogenesis genes, total BA and BA composition in the circulation and portal vein, and gut microbiota were examined. BD improves the metabolic phenotype, which is in accord with increased circulating primary BAs and regulation of enterohormones. BD-induced hypertrophy of the proximal intestine in the absence of BA was reversed by BA oral gavage, but without influencing BD metabolic benefits. BD-enhanced energy expenditure was associated with elevated TGR5, D2, and thermogenic genes, including UCP1, PRDM16, PGC-1α, PGC-1β, and PDGFRα in epididymal white adipose tissue (WAT) and inguinal WAT, but not in brown adipose tissue. BD resulted in an altered gut microbiota profile (i.e., Firmicutes bacteria were decreased, Bacteroidetes were increased, and Akkermansia was positively correlated with higher levels of circulating primary BAs). Our study demonstrates that enhancement of BA signaling regulates glucose and lipid homeostasis, promotes thermogenesis, and modulates the gut microbiota, which collectively resulted in an improved metabolic phenotype.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Pierre
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Martinez
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Honggang
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Anuradha
authors.initials: A
authors.lastname: Nadimpalli
authors.affiliation: Department of Ecology and Evolution, University of Chicago, Chicago, Illinois.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Morton
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois; and.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois; and.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Noelle
authors.initials: N
authors.lastname: Patno
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois; and dyin@surgery.bsd.uchicago.edu.
authors.forename: Deng Ping
authors.initials: DP
authors.lastname: Yin
mesh_terms: D054392:Adipokines / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism* / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005768:Gastrointestinal Hormones / Q000097:blood; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000382:microbiology; D007583:Jejunum / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood* / Q000382:microbiology / Q000503:physiopathology / Q000601:surgery; D010641:Phenotype; D015398:Signal Transduction; D022722:Thermogenesis
chemical_list: D054392:Adipokines; D001647:Bile Acids and Salts; D001786:Blood Glucose; D005768:Gastrointestinal Hormones; D008055:Lipids
keywords: bile acids; bile diversion; energy expenditure; gastric bypass; gut microbiota; mice; obesity