Circadian GLP-1 secretion in mice is dependent on the intestinal microbiome for maintenance of diurnal metabolic homeostasis

Abstract

The incretin, glucagon-like peptide-1 (GLP-1), is secreted by the intestinal L-cell upon nutrient ingestion. GLP-1 also exhibits a circadian rhythm, with highest release at the onset of the feeding period. Similarly, microbial composition and function exhibit circadian rhythmicity with fasting-feeding. The circadian pattern of GLP-1 release was found to be dependent upon the oral route of glucose administration and was necessary for the rhythmic release of insulin and diurnal glycemic control, in normal male and female mice. In mice fed a western (high-fat/high-sucrose) diet for 16wk, GLP-1 secretion was markedly increased but arrhythmic over the 24hr day, whereas levels of the other incretin, glucose-dependent insulinotrophic polypeptide were not as profoundly affected. Furthermore, the changes in GLP-1 secretion were shown to be essential for the maintenance of normoglycemia in this obesogenic environment. Analysis of the primary L-cell transcriptome, as well as of the intestinal microbiome, also demonstrated time-of-day- and diet-dependent changes paralleling GLP-1 secretion. Finally, studies in antibiotic-induced microbial-depletion, and in germ-free mice with and without fecal microbial transfer provided evidence for a role of the microbiome in diurnal GLP-1 release. In combination, these findings establish a key role for microbiome-dependent circadian GLP-1 secretion in the maintenance of 24-hour metabolic homeostasis.