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.

Electrochemical reduction of carbon dioxide (CO 2 ) is a viable solution for conversion of atmospheric CO 2 to value-added materials such as carbon monoxide (CO). In this project, a new urea iron-tetraphenylporphyrin-dimer (Fe-TPP-Dimer) was synthesized and applied for electrocatalytic CO 2 reduction under both homogeneous and heterogeneous conditions to selectively reduce CO 2 to CO. Immobilization of the catalyst onto carbon nanotubes (CNTs) in aqueous solution resulted in remarkable enhancement of its electrocatalytic abilities, with exceptional turnover frequencies (10 s À 1 ), high faradic efficiency (FE) of ∼ 90%, and a current density of 16 mA/cm 2 at À 0.88 V vs. RHE. This project exhibits the importance of molecular design in accessing heterogeneous applications with CNTs.Consumption of fossil fuels for energy production in recent decades has dispensed alarming amounts of carbon dioxide (CO 2 ), one of the leading contributors to climate change, into the atmosphere. [1][2][3][4][5] Although the capture and conversion of CO 2 to value-added synthons has become a desirable solution to this problem, challenges in regard to the species' general lack of reactivity and the costs associated with deployment and stability of such strategies remain prevalent. [6][7][8][9][10][11] In this respect, electrocatalytic CO 2 reduction reactions (CO 2 RRs) pose a promising alternative to this end. [12][13][14][15][16][17][18][19][20] Extensive research has been conducted on both homogeneous and heterogeneous molecular catalysts for CO 2 RR. [21][22][23][24] Although homogeneous catalysts are popular for CO 2 RR application, applying heterogeneous catalysts is essential for emerging of CO 2 to CO conversion in large scale. Additionally, most molecular catalysts favor non-aqueous solvents such as N,N-dimethylformamide (DMF) and acetonitrile, making them more costly to implement. [25][26][27] Immobilization of molecular catalysts onto electrode surfaces can occur via several methods which include covalent bonding, [28,29] non-covalent attachment, [30,31] and surface polymerization. , [32,33] Among them, non-covalent surface binding methods that capitalize on strong Van der Waals π-π interactions between carbon surfaces and polyaromatic hydrocarbon moieties is easily accomplished and displays great surface stability, [31,34] making it a favorable technique for immobilization. [30,[35][36][37][38] Carbon nanotubes (CNTs) are of particular interest for CO 2 electroreduction owing to their high stability, conductivity and large surface area. [19,31,[39][40][41][42] Among transition metal complexes, iron, [24,25,[43][44][45] cobalt [46][47][48] and nickel, [49][50][51] are prevailing and more environmentally friendly than other metals used for CO 2 RR application. Metalloporphyrin catalysts are attractive as molecular catalysts in this field because of their robust structure and their stability to harsh conditions such as high temperatures. [52] Demonstrative work by Savéant showed that iron tetraphenylporphyrin (Fe-TPP) complexe...

Circadian secretion of the incretin, glucagon-like peptide-1 (GLP-1), correlates with expression of the core clock gene, Bmal1, in the intestinal L-cell. Several SNARE proteins known to be circadian in pancreatic α- and β-cells are also necessary for GLP-1 secretion. However, the role of the accessory SNARE, Syntaxin binding protein-1 (Stxbp1; also known as Munc18-1) in the L-cell is unknown. The aim of this study was to determine whether Stxbp1 is under circadian regulation in the L-cell and its role in the control of GLP-1 secretion. Stxbp1 was highly-enriched in L-cells, and STXBP1 was expressed in a subpopulation of L-cells in mouse and human intestinal sections. Stxbp1 transcripts and protein displayed circadian patterns in mGLUTag L-cells line, while chromatin-immunoprecipitation revealed increased interaction between BMAL1 and Stxbp1 at the peak time-point of the circadian pattern. STXBP1 recruitment to the cytosol and plasma membrane within 30 minutes of L-cell stimulation was also observed at this time-point. Loss of Stxbp1 in vitro and in vivo led to reduced stimulated GLP-1 secretion at the peak time-point of circadian release, and impaired GLP-1 secretion ex vivo. In conclusion, Stxbp1 is a circadian regulated exocytotic protein in the intestinal L-cell that is an essential regulatory component of GLP-1 secretion.

Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small and large intestines, after 3, 7 and 10 weeks of treatment in male and female mice. Apraglutide (3mg/kg; 3-times per week) significantly increased small intestinal weight (p<0.001) and length (p<0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks (p<0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration (p<0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks (p<0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks (p<0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide demonstrates unexpected marked ability to increase intestinal length, as well as exerting time-and location-dependent specificity in its intestinotrophic actions. Significance: The novel long-acting GLP-2R agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time-and site-dependent fashion.

Intestinal functions demonstrate circadian rhythms thought to be entrained, in part, by an organisms’ intrinsic feeding and fasting periods as well as by the intestinal microbiome. Circadian disruption as a result of ill-timed nutrient exposure and obesogenic feeding poses an increased risk to disease. As such, the aim of this study was to assess the relationships between dietary timing, composition, and the microbiome with regard to rhythmic small intestinal structure and mucosal immunity. Rodent chow (RC)-mice exhibited time-dependent increases in small intestinal weight, villus height, and crypt depth as well as an increased proportion of CD8αα+ cells and concomitant decrease in CD8αβ+ cells at the onset of the feeding period (p < 0.05–0.001). Western diet (WD)-animals displayed disrupted time-dependent patterns in intestinal structure and lymphocyte populations (p < 0.05–0.01). Antibiotic-induced microbial depletion abrogated the time- and diet-dependent patterns in both RC- and WD-mice (p < 0.05–0.001). However, although germ-free-mice displayed altered rhythms, fecal microbial transfer from RC-mice was generally unsuccessful in restoring structural and immune changes in these animals. This study shows that adaptive changes in the small intestine at the onset of the feeding and fasting periods are disrupted by WD-feeding, and that these changes are dependent, in part, on the intestinal microbiome.

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.

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.

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