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 on 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 16 weeks, GLP-1 secretion was markedly increased but arrhythmic over the 24-h day, whereas levels of the other incretin, glucose-dependent insulinotropic 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 depleted 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-h metabolic homeostasis.

Association of Gut Hormones and Microbiota with Vascular Dysfunction in Obesity

“…Gut bacterial growth is constantly influenced by nutrient supply [230] and by the host chemical (digestive gastric and bile acid juices, digestive enzymes), and physical (intestinal peristalsis, colon contractions preparatory to bacteria elimination by defecation) factors.…”

Effects of Obesogenic Feeding and Free Fatty Acids on Circadian Secretion of Metabolic Hormones: Implications for the Development of Type 2 Diabetes

“…Nonetheless, circadian disruptors such as phase-shifts, as well as exposure to light during the normal rest period have been shown to disrupt the rhythms in GLP-1 release [ 63 , 66 ]. The use of rat and mouse models, which allows for identical fasting times as well as the delivery of a standard oral glucose load, showed that GLP-1 secretion follows a 24-h rhythm with peak secretion occurring at the onset of the normal active/feeding period, consistent with the role of nutrient intake as a zeitgeber for L cell rhythmicity [ 33 , 67 , 68 ]. Furthermore, analysis of primary mouse L cells, as well as of both murine (m) GLUTag and human NCI-H716 L cell lines has revealed the existence of a cell-autonomous circadian clock, as evidenced by anti-phasic expression of the positive and negative arms of the core molecular clock (i.e., Arntl and Per2 , respectively) [ 33 , 67 , 68 ].…”

“…Hence, more pronounced rhythms in insulin release are observed following oral rather than intravenous nutrient administration, consistent with the release of GLP-1 only following nutrient intake [ 69 ]. Furthermore, identical doses of GLP-1 in combination with the same glucose load result in differential insulin responses based on the time of day in both rat and mouse models [ 33 , 67 ]. GLP-1 receptor agonists have also been shown to synchronize rhythmic activity of pancreatic β cells in vitro [ 70 ].…”

“…However, given its actions stimulating the digestion and absorption of nutrients, including fatty acids [ 61 ], rhythmic release of GLP-2 is presumed to also contribute to the circadian control of metabolic homeostasis. Finally, the diurnal activity of the intestinal L cell has recently been shown to be dependent upon the intestinal microbiome [ 33 ] which, itself, demonstrates a circadian rhythm related to the fasting/feeding cycle [ 71 , 72 ]. Although specific microbial metabolites that regulate circadian L cell secretion have not been identified, short chain fatty acids and secondary bile acids also demonstrate circadian patterns [ 73 , 74 ] and are known L cell secretagogues [ 75 , 76 ].…”

“…In parallel with the human data, an abundance of work conducted using both genetic knockout approaches and rodent models of light-induced circadian disruption has demonstrated a mechanistic link between circadian rhythms and metabolism [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. However, over the last few years, in vivo studies as well as in vitro evidence also points to obesogenic diets and their components as disruptors of behavioral and metabolic circadian rhythmicity [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Although multiple circadian-related factors may synergize to promote disease, the major focus of this review will be the impact of fatty acids on the circadian function of two key metabolic cell types, the intestinal L cell that secretes glucagon-like peptide-1 (GLP-1), and the pancreatic β cell that releases insulin, as well as the mechanisms by which obesogenic diets may, ultimately, lead to metabolic dysfunction.…”