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

• Published in: The Journal of clinical investigation 2023-09, Vol.133 (18), p.1-19
• Main Authors: Frazier, Katya, Manzoor, Sumeed, Carroll, Katherine, DeLeon, Orlando, Miyoshi, Sawako, Miyoshi, Jun, St George, Marissa, Tan, Alan, Chrisler, Evan A, Izumo, Mariko, Takahashi, Joseph S, Rao, Mrinalini C, Leone, Vanessa A, Chang, Eugene B
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; BMAL1 protein; Carbohydrates; Circadian Clocks; Circadian rhythm; Circadian rhythms; Clock gene; Energy metabolism; Fatty acids; Forebrain; Gastrointestinal Microbiome; Gastrointestinal system; Gene deletion; Gene expression; Germfree; Gluconeogenesis; Glucose; Glucose metabolism; Health aspects; Homeostasis; Insulin resistance; Lipid Metabolism; Lipids; Liver; Metabolic disorders; Metabolic pathways; Metabolism; Metabolites; Mice; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Physiological aspects
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI162515

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.