TY - JOUR
T1 - Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis
AU - Worthmann, Anna
AU - John, Clara
AU - Rühlemann, Malte C.
AU - Baguhl, Miriam
AU - Heinsen, Femke Anouska
AU - Schaltenberg, Nicola
AU - Heine, Markus
AU - Schlein, Christian
AU - Evangelakos, Ioannis
AU - Mineo, Chieko
AU - Fischer, Markus
AU - Dandri, Maura
AU - Kremoser, Claus
AU - Scheja, Ludger
AU - Franke, Andre
AU - Shaul, Philip W.
AU - Heeren, Joerg
N1 - Funding Information:
This work was supported by grants funded by the Deutsche Forschungsgemeinschaft (SFB841).
Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - Adaptive thermogenesis is an energy-demanding process that is mediated by cold-activated beige and brown adipocytes, and it entails increased uptake of carbohydrates, as well as lipoprotein-derived triglycerides and cholesterol, into these thermogenic cells. Here we report that cold exposure in mice triggers a metabolic program that orchestrates lipoprotein processing in brown adipose tissue (BAT) and hepatic conversion of cholesterol to bile acids via the alternative synthesis pathway. This process is dependent on hepatic induction of cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) and results in increased plasma levels, as well as fecal excretion, of bile acids that is accompanied by distinct changes in gut microbiota and increased heat production. Genetic and pharmacological interventions that targeted the synthesis and biliary excretion of bile acids prevented the rise in fecal bile acid excretion, changed the bacterial composition of the gut and modulated thermogenic responses. These results identify bile acids as important metabolic effectors under conditions of sustained BAT activation and highlight the relevance of cholesterol metabolism by the host for diet-induced changes of the gut microbiota and energy metabolism.
AB - Adaptive thermogenesis is an energy-demanding process that is mediated by cold-activated beige and brown adipocytes, and it entails increased uptake of carbohydrates, as well as lipoprotein-derived triglycerides and cholesterol, into these thermogenic cells. Here we report that cold exposure in mice triggers a metabolic program that orchestrates lipoprotein processing in brown adipose tissue (BAT) and hepatic conversion of cholesterol to bile acids via the alternative synthesis pathway. This process is dependent on hepatic induction of cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) and results in increased plasma levels, as well as fecal excretion, of bile acids that is accompanied by distinct changes in gut microbiota and increased heat production. Genetic and pharmacological interventions that targeted the synthesis and biliary excretion of bile acids prevented the rise in fecal bile acid excretion, changed the bacterial composition of the gut and modulated thermogenic responses. These results identify bile acids as important metabolic effectors under conditions of sustained BAT activation and highlight the relevance of cholesterol metabolism by the host for diet-induced changes of the gut microbiota and energy metabolism.
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U2 - 10.1038/nm.4357
DO - 10.1038/nm.4357
M3 - Article
C2 - 28604703
AN - SCOPUS:85023645434
SN - 1078-8956
VL - 23
SP - 839
EP - 849
JO - Nature medicine
JF - Nature medicine
IS - 7
ER -