Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY(3-36NH2) (PYY(3-36NH2)) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY(3-36NH2) decreases food intake (FI) in rodents and humans; however, the exact mechanisms by which these peptides regulate FI remain unclear. Male C57BL/6 mice were injected (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY(3-36NH2) (0.03-3 microg), and FI was determined for up to 24 h. Ex4 and PYY(3-36NH2) alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), whereas a combination of the two peptides (0.06 microg Ex4 plus 3 microg PYY(3-36NH2)) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY(3-36NH2) delayed gastric emptying by a maximum of 19% (P < 0.01-0.001); however, there was no significant effect on locomotor activity nor was there induction of taste aversion. Capsaicin pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY(3-36NH2). Similarly, exendin-4(9-39) (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY(3-36NH2). Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY(3-36NH2) (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY(3-36NH2) suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY(3-36NH2)). These findings suggest that administration of low doses of Ex4 together with PYY(3-36NH2) may increase the suppression of FI without inducing significant side effects.
T he hormone glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L cells, which are localized in the distal ileum and colon (1), after nutrient ingestion (2-5). GLP-1 acts through a specific G-protein-coupled receptor to potently stimulate glucose-dependent insulin secretion (6 -8). GLP-1 further reduces glycemia through inhibition of both glucagon secretion (9) and gastric emptying (10) and by stimulation of pancreatic -cell proliferation and neogenesis (11,12). The GLP-1 receptor is also expressed in hypothalamic nuclei that are responsible for modulating feeding behavior (13,14), and central GLP-1 administration reduces food intake in rodents, whereas peripheral administration of GLP-1 promotes satiety and decreases body weight in humans (13,15). These pleiotropic actions of GLP-1 therefore offer great potential for the treatment of hyperglycemia in patients with type 2 diabetes (1,15).It has recently been shown that plasma GLP-1 levels are reduced in obesity (16 -19), a condition that is highly correlated to type 2 diabetes (20). The mechanisms leading to decreased GLP-1 secretion in obesity have not been elucidated. However, because plasma leptin levels are proportional to fat mass, we postulated the existence of an adipo-enteroendocrine interaction between leptin and GLP-1. Leptin, a product of the ob gene in white adipose tissue, activates hypothalamic circuits, leading to the inhibition of food intake (21,22). The leptin receptor gene encodes five alternatively spliced forms of mRNA (23,24). However, only the long form of the leptin receptor (ObRb) contains an intracellular JAK-STAT signaling motif, and Ob-Rb appears to be responsible for the physiological actions of leptin (25-27). Although Ob-Rb is predominantly distributed in the ventral medial hypothalamic region known to be important in determining feeding behavior (21,28), it is now recognized that Ob-Rb is also expressed in several peripheral tissues, including the gut and the pancreas (29 -31).It has been shown that ob/ob mice, which are homozygous for a mutation of the ob gene, and db/db mice, which have a mutation in the leptin receptor, both exhibit hyperphagia and morbid obesity, leading to hyperinsulinemia and hyperglycemia (22,23). Although ob/ob and db/db mice serve as models of type 2 diabetes, human ob or db gene mutations are extremely rare, and no linkages with diabetes have been found (32,33). Nonetheless, most obese humans exhibit hyperleptinemia, and increased adiposity is believed to occur in association with the development of leptin resistance (21,32,33). One model of leptin resistance is the C57BL/6 mouse submitted to a high-fat diet (34). In contrast to the ob/ob and db/db mice, these mice develop impaired glucose tolerance but seldom progress to frank diabetes. We now demonstrate that leptin stimulates GLP-1 secretion from enteroendocrine L cells in vitro and in vivo and, furthermore, that leptin resistance in obese C57BL/6 mice is associated with impaired secretion of GLP-1. RESEARCH DESIGN AND METHODSCell cultu...
Short-chain fatty acids (SCFAs) are recognized as the major anions of the large intestinal content in humans, but their effect on colonic motility is controversial. This study explores the colonic motor effect of SCFAs and their mechanisms in the rat. Colonic motility (electromyography) and transit time (plastic markers) were measured in conscious rats while SCFAs were infused into the colon, either alone or after administration of neural antagonists or immunoneutralization of circulating polypeptide YY (PYY). SCFA-induced PYY release was measured by RIA and then simulated by infusing exogenous PYY. Intracolonic infusion of 0.4 mmol/h SCFAs had no effect, whereas 2 mmol/h SCFAs reduced colonic motility (36 ± 3 vs. 57 ± 4 spike bursts/h with saline, P< 0.05) by decreasing the ratio of nonpropulsive to propulsive activity. This resulted in an increased transit rate ( P < 0.01). Neither α-adrenoceptor blockade nor nitric oxide synthase inhibition prevented SCFA-induced motility reduction. Intraluminal procaine infusion suppressed the SCFA effect, indicating that a local neural mechanism was involved. SCFA colonic infusion stimulated PYY release in blood. Immunoneutralization of circulating PYY abolished the effect of SCFAs on colonic motility, whereas exogenous PYY infusion partly reproduced this effect. SCFAs modify colonic motor patterns in the rat and increase transit rate; local nerve fibers and PYY are involved in this effect.
Apelin is a recently discovered peptide that is the endogenous ligand for the APJ receptor. The aim of this study was to characterize apelin expression (mRNA levels) in the rat gastrointestinal tract and pancreas, to localize distribution of apelin peptide-containing cells in the stomach by immunohistochemistry, and to characterize the ontogeny of gastric apelin expression and peptide and the influence of apelin on gastric cell proliferation in vitro. Additionally, the effect of apelin on cholecystokinin (CCK) secretion and the involvement of MAPK, protein kinase C, and changes in intracellular Ca(2+) in apelin-induced CCK secretion in vitro were examined. Northern analysis showed a maximal apelin expression in the stomach with a lower expression level in the intestine. Apelin expression was not detected in the pancreas. Immunohistochemistry revealed abundant apelin-positive cells in the glandular epithelium of the stomach. The ontogeny study showed a higher apelin expression in the fetal and postnatal rat stomachs when compared with the adult stomach. In contrast to apelin expression, apelin peptide was not detected in the rat stomach until 20 d of age and then increased progressively with age. Apelin was shown to stimulate gastric cell proliferation in vitro. Apelin also stimulated CCK secretion from a murine enteroendocrine cell line (STC-1); apelin-stimulated CCK secretion is mediated through MAPK but not by intracellular Ca(2+) signaling. Together, these data indicate that apelin is an important new stomach peptide with a potential physiological role in the gastrointestinal tract.
The proglucagon-derived peptide family consists of three highly related peptides, glucagon and the glucagon-like peptides GLP-1 and GLP-2. Although the biological activity of glucagon as a counter-regulatory hormone has been known for almost a century, studies conducted over the past decade have now also elucidated important roles for GLP-1 as an antidiabetic hormone, and for GLP-2 as a stimulator of intestinal growth. In contrast to pancreatic glucagon, the GLPs are synthesized in the intestinal epithelial L cells, where they are subject to the influences of luminal nutrients, as well as to a variety of neuroendocrine inputs. In this review, we will focus on the complex integrative mechanisms that regulate the secretion of these peptides from L cells, including both direct and indirect regulation by ingested nutrients.
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