Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.
Details
Title
Gut microbes and the liver circadian clock partition glucose and lipid metabolism
Author
Frazier, Katya : University of Chicago Manzoor, Sumeed : University of Chicago Carroll, Katherine : University of Chicago DeLeon, Orlando : University of Chicago Miyoshi, Sawako : Kyorin University Miyoshi, Jun : Kyorin University St. George, Marissa : University of Chicago Tan, Alan : University of Chicago Chrisler, Evan A. : University of Wisconsin-Madison Izumo, Mariko : University of Texas Takahashi, Joseph S. : University of Texas Rao, Mrinalini C. : University of Chicago Leone, Vanessa A. : University of Wisconsin-Madison Chang, Eugene B. : University of Chicago
Content Type
Article
Published in
The Journal of Clinical Investigation
Data availability statement
16S rRNA sequences are available for download at the NCBI Sequence Read Archive (accession PRJNA815335). RNA sequences are available for download at the NCBI Gene Expression Omnibus (accession GSE184303).
Funding Information
National Institute of Diabetes and Digestive and Kidney Diseases, R01DK115221 National Institute of Diabetes and Digestive and Kidney Diseases, P30DK42086 National Institute of Diabetes and Digestive and Kidney Diseases, K01DK111785 National Institute of Diabetes and Digestive and Kidney Diseases, F31DK122714 National Institute of Diabetes and Digestive and Kidney Diseases, T32DK070774 University of Chicago, GI Research Foundation