Gut microbes and the liver circadian clock partition glucose and lipid metabolism
Katya Frazier, Sumeed Manzoor, Katherine Carroll, Orlando DeLeon, Sawako Miyoshi, Jun Miyoshi, Marissa St. George, Alan Tan, Evan A. Chrisler, Mariko Izumo, Joseph S. Takahashi, Mrinalini C. Rao, Vanessa A. Leone, Eugene B. Chang
Katya Frazier, Sumeed Manzoor, Katherine Carroll, Orlando DeLeon, Sawako Miyoshi, Jun Miyoshi, Marissa St. George, Alan Tan, Evan A. Chrisler, Mariko Izumo, Joseph S. Takahashi, Mrinalini C. Rao, Vanessa A. Leone, Eugene B. Chang
View: Text | PDF
Research Article Metabolism

Gut microbes and the liver circadian clock partition glucose and lipid metabolism

Abstract

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.

Authors

Katya Frazier, Sumeed Manzoor, Katherine Carroll, Orlando DeLeon, Sawako Miyoshi, Jun Miyoshi, Marissa St. George, Alan Tan, Evan A. Chrisler, Mariko Izumo, Joseph S. Takahashi, Mrinalini C. Rao, Vanessa A. Leone, Eugene B. Chang

×

Figure 2

Modulation of gut microbes can both eliminate and restore liver clock–mediated GNG.

Options: View larger image (or click on image) Download as PowerPoint
Modulation of gut microbes can both eliminate and restore liver clock–me...
(A) PTT in WT and LKO male mice before (Pre-Abx) and after (Post-Abx) daily antibiotic treatment for 2 weeks (n = 12–13/group). The graph represents the AUC. (B) PTT in GF WT male mice conventionalized with fecal microbes from SPF WT or LKO male mice (n = 11–12/group). (C) PTT in GF WT and LKO male mice conventionalized with fecal microbes from SPF WT male mice (n = 15–16/group). Inset graphs represents AUC normalized to baseline glucose. Data points represent mean ± SEM. Lines in box plots represent the median, and whiskers represent the minimum and maximum, respectively. Two-tailed unpaired Welch’s t tests were performed between 2 groups; Brown-Forsythe and Welch’s ANOVA followed by Dunnett’s tests were performed between 3 or more groups. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, relative to Pre-Abx WT.