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Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 hours were measured using a thermocouple thermometer before and after an oral administration of nutrients. Oxygen consumption after oral protein administration was also measured in rats. Rectal temperature measurements in rats confirmed an increase in core body temperature after refeeding, and the thermic effect of the oral administration of protein was greater than that of a representative carbohydrate or lipid. Among the five dietary proteins examined (casein, whey, rice, egg, and soy), soy protein had the highest thermic effect. The thermic effect of soy protein was also demonstrated by increased oxygen consumption. Studies using a nonselective beta-adrenergic receptor antagonist and thermal camera suggested that brown adipose tissue did not contribute to soy protein-induced increase in rectal temperature. Furthermore, the thermic effect of soy protein was completely abolished by antagonism and knockout of the GLP-1 receptor, yet potentiated via augmentation of intact GLP-1 levels through inhibition of dipeptidyl peptidase-4 activity. These results indicate that GLP-1 signaling is essential for the thermic effects of dietary proteins in rats and mice, and extend the metabolic actions of GLP-1 ensuing from nutrient ingestion to encompass the thermic response to ingested protein.

Dietary peptides potently stimulate glucagon-like peptide-1 (GLP-1) secretion, however, the underlying molecular mechanisms, such as structure-activity relationships and sensing mechanisms are only partly elucidated. In this study, we used a dipeptide library to identify dipeptides that potently stimulate GLP-1 release and to clarify the underlying structure-activity relationship. Murine enteroendocrine GLUTag cells were exposed to 339 dipeptides for 60 min, and the concen-tration of GLP-1 released into the supernatant was measured. Subsequently, selected dipeptides were examined for their reproducibility and dose responsiveness. In addition, we investigated the role of constituent amino acids in the secretion of GLP-1, and whether tripeptides containing the active dipeptide structures maintained their activity. In a concentration range of 1-5 mg/mL, twelve dipeptides had reproducible and concentration-dependent GLP-1-releasing activity. Among them, nine dipeptides (FY, KF, NI, PM, QL, QY, WF, WN, WY) were novel, with WY exhibiting the most potent activity. The reverse sequences and most free amino acids did not induce GLP-1 secretion, indicating that GLP-1-producing cells recognize the struc-ture of each peptide to induce GLP-1 secretion. However, no apparent similarities were found between the active peptides. A comparison between the six tripeptides composed of F, W, and Y revealed the further potent tripeptides FWY and WYF, than WY. In the present study, a comprehensive analysis revealed nine novel dipeptides with high potential to stimulate GLP-1 secretion. Furthermore, the results indicate that 'WY' is a specific dipeptide sequence that potently stimulates GLP-1 secretion. & COPY; 2023 Elsevier Inc. All rights reserved.

Live-cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon-like peptide-1 (GLP-1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP-1 synthesis through the post-translational processing from proglucagon. Here, we have developed FP-tagged GLP-1 by inserting FPs into the middle of GLP-1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP-1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP-tagged GLP-1 enables direct visualization of stimulation-dependent exocytosis of GLP-1 at a single granule resolution with total internal reflection fluorescence microscopy. FP-tagged GLP-1 might facilitate the screening of GLP-1 secretagogues and the discovery of new antidiabetic drugs.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes. View Full-Text

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes. View Full-Text

This study examined the effects of a combination of soybean fiber and alpha-glycosyl-isoquercitrin (AGIQ) on improving quercetin bioavailability and glucose metabolism in rats fed an obesogenic diet. For 9 weeks, rats were individually fed a control diet, a high-fat high-sucrose (H) diet, H with soybean fiber (HS), or with AGIQ (HQ), or with both (HSQ). Quercetin derivatives in plasma, feces, urine, and cecal content were quantified by high-performance liquid chromatography to assess the bioavailability of quercetin, and meal tolerance tests were performed to assess postprandial glycemia and glucagon-like peptide-1 (GLP-1) responses. The HSQ group had higher plasma quercetin levels than HQ. The postprandial glycemia was attenuated in the HSQ group when compared to the H group. The basal plasma GLP-1 concentrations positively correlated with plasma quercetin derivative concentrations. Hence, the combination of soybean fiber and AGIQ could be beneficial for reducing the risk of glucose intolerance, possibly involving enhanced quercetin bioavailability and GLP-1 secretion.

Glucagon-like peptide-1 (GLP-1) is postprandially secreted from enteroendocrine L-cells and enhances insulin secretion. Currently, it is still controversial whether postprandial GLP-1 responses are altered in obesity and diabetes. To address the issue and to find out possible factors related, we compared postprandial GLP-1 responses in normal rats and in diabetic rats chronically fed an obesogenic diet. Male Wistar rats and diabetic Goto-Kakizaki (GK) rats were fed either a control diet or a high-fat/high-sucrose (HFS, 30 % fat and 40 % sucrose) diet for 26 weeks. Meal tolerance tests were performed for monitoring postprandial responses after a liquid diet administration (62 center dot 76 kJ/kg body weight) every 4 or 8 weeks. Postprandial glucose, GLP-1 and insulin responses in Wistar rats fed the HFS diet (WH) were higher than Wistar rats fed the control diet (WC). Although GK rats fed the HFS diet (GH) had higher glycaemic responses than GK rats fed the control diet (GC), these groups had similar postprandial GLP-1 and insulin responses throughout the study. Jejunal and ileal GLP-1 contents were increased by the HFS diet only in Wistar rats. Furthermore, mRNA expression levels of fatty acid receptors (Ffar1) in the jejunum were mildly (P = 0 center dot 053) increased by the HFS diet in Wistar rats, but not in GK rats. These results demonstrate that postprandial GLP-1 responses are enhanced under an obesogenic status in normal rats, but not in diabetic rats. Failure of adaptive enhancement of GLP-1 response in GK rats could be partly responsible for the development of glucose intolerance.

The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to "meal ingestion" under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.

The present study was conducted to examine region-dependent glucagon-like peptide-1 (GLP-1) responses to "meal ingestion" under physiological (conscious and unrestrained) conditions using rats with a catheter inserted into either the portal vein (PV) or the ileal mesenteric vein (ILMV). After recovery from the cannulation surgery, blood samples were collected from either PV or ILMV catheter before and after the voluntary ingestion of test diets. After an AIN-93G standard diet ingestion, GLP-1 concentration was higher in ILMV than in PV, and postprandial responses of peptide-YY (PYY) had similar trend, while that of glucose dependent-insulinotropic polypeptide showed an opposite trend to GLP-1/PYY responses. In a separated experiment, a protein-enriched diet containing casein at 25% wt/wt transiently increased GLP-1 concentration only in ILMV; however, a protein-free diet did not increase GLP-1 concentrations in PV or ILMV. These results indicate that postprandial GLP-1 is immediately released from the distal intestine under physiological conditions, and that dietary protein has a critical role in the enhancement of postprandial GLP-1 response.