Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas (original) (raw)
Related papers
Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents
American Journal of Physiology-Gastrointestinal and Liver Physiology
A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrat...
Frontiers in Endocrinology
PurposeDecreased circulating levels of food-intake-regulating gut hormones have been observed in type 2 diabetes and obesity. However, it is still unknown if this is due to decreased secretion from the gut mucosal cells or due to extra-intestinal processing of hormones.MethodsWe measured intestinal hormone content and assessed morphological differences in the intestinal mucosa by histology and immunohistochemistry. Secretion of hormones and absorption of glucose and bile acids (BA) were assessed in isolated perfused mouse intestine.ResultsGIP (glucose-dependent insulinotropic polypeptide) and SS (somatostatin) contents were higher in the duodenum of control mice (p < 0.001, and <0.01). Duodenal GLP-1 (glucagon-like peptide-1) content (p < 0.01) and distal ileum PYY content were higher in DIO mice (p < 0.05). Villus height in the jejunum, crypt depth, and villus height in the ileum were increased in DIO mice (p < 0.05 and p = 0.001). In the distal ileum of DIO mice, mo...
Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice
Drug Metabolism and Disposition, 2015
It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2-to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12a-OH BAs, namely, b-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter a, and organic solute transporter b) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12a-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.
Endocrinology, 1998
Intraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileocolonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)-(7-36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 Ϯ 4% (P Ͻ 0.001) and increased plasma levels of GLP-1 and PYY by 44 Ϯ 5 and 46 Ϯ 4 fmol/ml, respectively (both P Ͻ 0.01). Pretreatment with the CCK-A receptor antagonist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 Ϯ 4 fmol/ml), and reduced plasma PYY responses to baseline. Intravenous infusions of 50 pmol/ kg⅐h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 Ϯ 5% and 51 Ϯ 6%, respectively (both P Ͻ 0.01); coinfusions of GLP-1 and PYY abolished gastric acid secretion (P Ͻ 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg⅐h of the GLP-1 antagonist exendin-(9-39) amide did not alter the magnitude of inhibition of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK-dependent pathways, are major enterogastrones in dogs. This inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects. (Endocrinology 139: 189-194, 1998)
Journal of agricultural and food chemistry, 2012
Gastrointestinal (GI) peptide hormones play an important role in short-term regulation of food intake and blood glucose levels. Modulating their release is of potential relevance for weight management and possibly diabetes. As currently available models are hard to extrapolate to the human situation, the use of porcine intestinal tissue, collected from slaughter pigs, was investigated for this purpose. Intestinal tissue disks showed a predicted regional release pattern of GI peptides. Various longchain fatty acids differentially stimulated release of glucagon-like peptide 1 (GLP-1) (up to 500%) and glucagon-like peptide 2 (GLP-2) (up to 200%) from ileal tissue disks, but effects on peptide YY (PYY) did not reach significance. Short-chain fatty acids had no effects on the release of GLP-1, GLP-2, and PYY in either the ileum or colon. In conclusion, this porcine tissue model shows to be of advantageous use in a tiered approach to study the potential of satiety-inducing compounds to be selected for studies in humans.
Gut, 2020
ObjectivesLipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1–/– mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation.DesignWe evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1–/– mice. We assessed the role of the fat receptor GPR119 in these effects using G...
Short-chain fatty acids and regulation of pancreatic endocrine secretion in mice
Islets, 2019
The intestinal microbiota has been demonstrated to influence host metabolism, and has been proposed to affect the development of obesity and type 2 diabetes (T2D), possibly through shortchain fatty acids (SCFAs) produced by fermentation of dietary fiber. There are some indications that SCFAs inhibit glucose-stimulated insulin secretion (GSIS) in rodents, but research on this subject is sparse. However, it has been reported that receptors for SCFAs, free fatty acid receptor 2 (FFAR2) and FFAR3 are expressed not only on gut endocrine cells secreting GLP-1 and PYY, but also on pancreatic islet cells. We hypothesized that SCFAs might influence the endocrine secretion from pancreatic islets similar to their effects on the enteroendocrine cells. We studied this using isolated perfused mouse pancreas which responded adequately to changes in glucose and to infusions of arginine. None of the SCFAs, acetate, propionate and butyrate, influenced glucagon secretion, whereas they had weak inhibitory effects on somatostatin and insulin secretion. Infusions of two specific agonists of FFAR2 and FFAR3, CFMB and Compound 4, respectively, did not influence the pancreatic secretion of insulin and glucagon, whereas both induced strong increases in the secretion of somatostatin. In conclusion, the small effects of acetate, propionate and butyrate we observed here may not be physiologically relevant, but the effects of CFMB and Compound 4 on somatostatin secretion suggest that it may be possible to manipulate pancreatic secretion pharmacologically with agonists of the FFAR2 and 3 receptors, a finding which deserves further investigation.
Regulation of food intake by gastrointestinal hormones
Current Opinion in Gastroenterology, 2006
Purpose of review Complex physiological mechanisms have evolved to control food intake in mammals, which in health ensure the relative stability of body weight in adults. Central brain centres, gutderived peptides and adipose-derived signals result in an integrative response to defend against starvation. Enteroendocrine cells throughout the gut and pancreas secrete a number of peptides with activity on gut motility, gut secretions and appetite. Understanding the interactions between different gut peptides has produced a rewardingly active research field with many unanswered questions. Recent findings Many gut peptides are now in translational research programmes to investigate their potential in human physiology and disease. Ghrelin has been shown in shortterm human studies to both increase appetite and body weight. Oxyntomodulin has been shown to reduce weight and food intake in a 4 week study in humans. Anorectic activity of peptide YY 3-36 has been confirmed in a number of animal models. Obestatin has been identified as a novel gut peptide. Increasing evidence points to the effect of gastricbypass surgery on body weight, including alteration of gut peptide activity. Summary Gut peptides, or gut-peptide mimetics, show great promise for use as therapeutic agents for the treatment of obesity and cachexia.