TY - JOUR
T1 - Assessment of the role of FGF15 in mediating the metabolic outcomes of murine vertical sleeve gastrectomy
AU - Myronovych, Andriy
AU - Bhattacharjee, Jashdeep
AU - Salazar-Gonzalez, Rosa Maria
AU - Tan, Brandon
AU - Mowery, Sarah
AU - Ferguson, Danielle
AU - Ryan, Karen K.
AU - Zhang, Wujuan
AU - Zhao, Xueheng
AU - Oehrle, Melissa
AU - Setchell, Kenneth D.R.
AU - Seeley, Randy J.
AU - Sandoval, Darleen A.
AU - Kohli, Rohit
N1 - Publisher Copyright:
© 2020 American Physiological Society. All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its comorbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in humans and its murine ortholog Fgf15 play a pivotal role in this bile acid-driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15-deficient (KO) mice. 6- to 8-wk-old male wild-type (WT) and KO mice were fed a high-fat diet (HFD) for 8 wk. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Postsurgery, mice were observed for 8 wk while fed a HFD and then euthanized to collect tissues for experimental analysis. KO mice lost weight post-VSG, but glucose tolerance in KO mice did not improve post-VSG compared with WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post-VSG, both WT and KO mice had similarly altered bile acid enterohepatic flux; however, Fgf15 deficient mice post-VSG had increased hepatic accumulation of free and esterified cholesterol, leading to lipotoxicity-related endoplasmic reticulum stress, inflammasome activation, and increased Fgf21 expression. We conclude that intact Fgf15-mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared with their canonical downstream signaling pathways. NEW & NOTEWORTHY In the absence of an intact fibroblast growth factor 15 (FGF15) signaling pathway, murine vertical sleeve gastrectomy results in weight loss without all its anticipated metabolic benefits. In the absence of an intact FGF15 signaling pathway, vertical sleeve gastrectomy results in increased intestinal bile acid levels and hepatolipotoxicity.
AB - Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its comorbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in humans and its murine ortholog Fgf15 play a pivotal role in this bile acid-driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15-deficient (KO) mice. 6- to 8-wk-old male wild-type (WT) and KO mice were fed a high-fat diet (HFD) for 8 wk. At 8th week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Postsurgery, mice were observed for 8 wk while fed a HFD and then euthanized to collect tissues for experimental analysis. KO mice lost weight post-VSG, but glucose tolerance in KO mice did not improve post-VSG compared with WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post-VSG, both WT and KO mice had similarly altered bile acid enterohepatic flux; however, Fgf15 deficient mice post-VSG had increased hepatic accumulation of free and esterified cholesterol, leading to lipotoxicity-related endoplasmic reticulum stress, inflammasome activation, and increased Fgf21 expression. We conclude that intact Fgf15-mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared with their canonical downstream signaling pathways. NEW & NOTEWORTHY In the absence of an intact fibroblast growth factor 15 (FGF15) signaling pathway, murine vertical sleeve gastrectomy results in weight loss without all its anticipated metabolic benefits. In the absence of an intact FGF15 signaling pathway, vertical sleeve gastrectomy results in increased intestinal bile acid levels and hepatolipotoxicity.
KW - Cholesterol metabolism
KW - Glucose tolerance
KW - Hepatic lipid metabolomics
KW - Liver injury
KW - Serum bile acid composition
UR - http://www.scopus.com/inward/record.url?scp=85098072730&partnerID=8YFLogxK
U2 - 10.1152/AJPGI.00175.2020
DO - 10.1152/AJPGI.00175.2020
M3 - Article
C2 - 32967428
AN - SCOPUS:85098072730
SN - 0193-1857
VL - 319
SP - G669-G684
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 6
ER -