Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY, resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.

Gut endocrine cells are generally thought to have distinct localization and secretory products. Recent studies suggested that the cells are highly related and have potential to express more than one hormone. We studied the coexpression and cosecretion of gut hormones in separate segments of rat small intestine. We measured secretion of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), neurotensin, glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) from proximal and distal half of the small intestine, isolated from male rats and perfused ex vivo. Hormone secretion was stimulated by bombesin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, and peptones. Furthermore, tissue samples collected along the intestine were analyzed for expression, hormone content, and cell densities including colocalization. Most hormones responded to all three stimuli (but no GIP response to bombesin). GLP-1 secretion was similar from proximal and distal intestine, whereas PYY was secreted only from the distal half. CCK and GIP were mainly secreted proximally, whereas neurotensin was equally secreted from both parts. Cell densities, hormone concentrations, and expression patterns were generally parallel, with increasing values distally for GLP-1 and PYY, an exclusively proximal pattern for CCK, even distribution for neurotensin and GIP except for the most distal segments. PYY nearly always colocalized with GLP-1. Approximately 20% of GLP-1 cells colocalized with CCK and neurotensin, whereas GLP-1/GIP colocalization was rare. Our findings indicate that two L cell types exist, a proximal one secreting GLP-1 (and possibly CCK and neurotensin), and a distal one secreting GLP-1 and PYY. GIP seems to be secreted from cells that are not cosecreting other peptides.

BackgroundMice, rats, and pigs are the three most used animal models when studying gastrointestinal peptide hormones; however their distribution from the duodenum to the distal colon has not been characterized systematically across mice, rats and pigs. We therefore performed a comparative distribution analysis of the tissue content of the major appetite- and glucose regulatory peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 (GLP-2), oxyntomodulin/glicentin, neurotensin, and peptide YY (PYY) from the duodenum to distal colon in mice (n = 9), rats (n = 9) and pigs (n = 8), using validated radioimmunoassays.ResultsGLP-1, GLP-2 and oxyntomodulin/glicentin show similar patterns of distribution within the respective species, but for rats and pigs the highest levels were found in the distal small intestine, whereas for the mouse the highest level was found in the distal colon. In rats and pigs, neurotensin was predominantly detected in mid and lower part of the small intestine, while the mouse showed the highest levels in the distal small intestine. In contrast, the distribution of GIP was restricted to the proximal small intestine in all three species. Most surprisingly, in the pig PYY was found in large amounts in the proximal part of the small intestine whereas both rats and mice had undetectable levels until the distal small intestine.ConclusionsIn summary, the distribution patterns of extractable GIP, GLP-1, GLP-2, oxyntomodulin/glicentin, neurotensin are preserved across species whereas PYY distribution showed marked differences.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-016-1872-2) contains supplementary material, which is available to authorized users.

Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1), is inactivated by the same protease (dipeptidyl peptidase-4) as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides.

Weight loss induced by endurance exercise is often disappointing, possibly due to an increase in energy intake mediated through greater appetite. The aim of this study was to evaluate fasting, postprandial, and postexercise appetite regulation after an intervention prescribing two amounts of endurance exercise. Sixty-four sedentary, overweight, healthy young men were randomized to control (CON), moderate-dose (MOD: ≈ 30 min/day), or high-dose (HIGH: ≈ 60 min/day) endurance exercise for 12 wk. Along with subjective appetite ratings, plasma ghrelin, glucagon, insulin, peptide YY3-36, glucose, free fatty acids, and glycerol were measured during fasting and in relation to a breakfast meal and an acute bout of exercise, both at baseline and at follow-up. Ad libitum lunch energy intake was evaluated 3 h after the breakfast meal. Despite different amounts of endurance exercise, the subjects lost similar amounts of fat mass (MOD: 4.2 ± 0.5 kg; HIGH: 3.7 ± 0.5 kg). Fasting and postprandial insulin decreased ≈ 20% in both exercise groups (P < 0.03 vs. CON). Appetite measurements were not upregulated in the fasting and postprandial states. On the contrary, fasting and postprandial ratings of fullness and postprandial PYY3-36 increased in HIGH (P < 0.001 vs. CON). Ad libitum lunch energy intake remained unchanged over the course of the intervention. In both exercise groups, plasma ghrelin increased in relation to acute exercise after training. Thus neither moderate nor high doses of daily endurance exercise increased fasting and postprandial measures of appetite, but a high dose of exercise was associated with an increase in fasting and meal-related ratings of fullness and satiety.

CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

-Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH 2 terminally truncated metabolite, PYY3-36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY 1-36 and PYY3-36 in eight young, healthy men. A metabolite, corresponding to PYY 3-34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY 3-34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY 1-36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 Ϯ 0.5 and 9.4 Ϯ 0.8 min (means Ϯ SE) and metabolic clearance rates of 15.7 Ϯ 1.5 and 14.1 Ϯ 1.1 ml·kg Ϫ1 ·min Ϫ1 after infusion, whereas PYY 3-36 was eliminated with a significantly longer half-life of 14.9 Ϯ 1.3 min and a metabolic clearance rate of 9.4 Ϯ 0.6 ml·kg Ϫ1 ·min Ϫ1 . We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOHterminal amino acids. In healthy men, PYY 3-36 has a longer half-life than PYY 1-36. peptide YY; kinetics; degradation PEPTIDE YY (PYY) is a gastrointestinal peptide hormone, released into the circulation in response to food intake (3,4,8,18), belonging to the pancreatic polypeptide family together with neuropeptide Y (NPY) and pancreatic polypeptide. These are all 36-amino-acid peptides characterized by a high content of tyrosine, proline, and arginine and a hairpin structure, the so-called " 21).PYY is synthesized and released from endocrine L-cells in the intestinal mucosa, often together with proglugacon-derived peptides, namely glucagon-like peptide-1 (GLP-1), GLP-2, oxyntomodulin, and glicentin. PYY immunoreactive cells are found primarily in ileum and colon with increasing density distally (4).PYY is present in plasma in two major molecular forms, the 36-amino-acid form, PYY 1-36 , and the 34-amino-acid NH 2 -terminally truncated form, PYY 3-36 , which is formed by cleavage of the two NH 2 -terminal amino acids by the enzyme dipeptidyl peptidase-4 (DPP-4) (28). DPP-4 is present in both a soluble form and as a transmembrane protein in endothelial, epithelial, and lymphoid tissue. DPP-4 cleaves and inactivates, e.g., glucose-dependent insulinotropic polypeptide and GLP-1 with short plasma half-lives of 5 and 1-2 min, respectively (15,23,36).Anorexigenic effects of PYY 3-36 have been demonstrated in several studies with intravenous administration of PYY 3-36 (6, 16, 32, 34), whereas infusions of PYY 1-36 have no effect on food intake (34), suggesting that the cleavage of PYY 1-36 to PYY 3-36 is not as complete and rapid as for GLP-1 (34). The half-life of PYY 1-36 has been deter...

Peptide YY (PYY) is a 36 amino acid peptide hormone released from enteroendocrine cells. An N-terminally degraded metabolite, PYY3–36, has anorexigenic effects, which makes the PYY system a target for obesity treatment. However, little is known about the kinetics and degradation products of PYY. A related peptide, Neuropeptide Y (NPY), may be degraded from the C-terminus. We therefore investigated PYY degradation after in vitro incubations in porcine plasma and blood and in vivo by infusing PYY3–36 into multicatheterized pigs (n = 7) (2 pmol/kg/min). Plasma samples were analyzed by region-specific radioimmunoassays (RIA) and HPLC analysis. A metabolite, corresponding to PYY3–34 was formed after incubation in plasma and blood and during the infusion study. When taking the C-terminal degradation into account, the half-life (T½) of PYY in blood and plasma amounted to 3.4 ± 0.2 and 6.2 ± 0.2 h, respectively. After PYY3–36 infusion in pigs, the peptide was degraded with a T½ of 3.6 ± 0.5 min. Significant extraction (20.5 ± 8.0%) compatible with glomerular filtration was observed across the kidneys and significant C-terminal degradation (26.5 ± 4.8%) was observed across the liver. Net balances across the hind limb, splanchnic bed, and lungs were not significantly different from zero. PYY3–34 was unable to activate the Y2 receptor in a transfected cell line. In conclusion, PYY3–36 is extensively degraded to PYY3–34 in the pig, a degradation that renders the peptide inactive on the Y2 receptor. Currently used assays are unlikely to be able to detect this degradation and therefore measure falsely elevated levels of PYY3–36, leading to underestimation of its physiological effects.