Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis

Nat Med. 2017 Jul;23(7):839-849. doi: 10.1038/nm.4357. Epub 2017 Jun 12.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adipose Tissue, Brown / metabolism
  • Alanine Transaminase / metabolism
  • Animals
  • Aspartate Aminotransferases / metabolism
  • Bile Acids and Salts / metabolism*
  • Blotting, Western
  • Calorimetry, Indirect
  • Case-Control Studies
  • Cholesterol / metabolism*
  • Cold Temperature*
  • Cytochrome P450 Family 7 / genetics
  • Cytochrome P450 Family 7 / metabolism
  • Gastrointestinal Microbiome* / genetics
  • Gene Expression Profiling
  • Humans
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Obesity
  • RNA, Ribosomal, 16S / genetics
  • Receptors, LDL / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Thermogenesis*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Bile Acids and Salts
  • P-glycoprotein 2
  • RNA, Ribosomal, 16S
  • Receptors, LDL
  • Cholesterol
  • Steroid Hydroxylases
  • Cytochrome P450 Family 7
  • Cyp7b1 protein, mouse
  • Aspartate Aminotransferases
  • Alanine Transaminase