Peptides (v.77, #C)

Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans by Catherine Gibbons; Graham Finlayson; Phillipa Caudwell; Dominic-Luc Webb; Per M. Hellström; Erik Näslund; John E. Blundell (3-8).
CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited.First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size).Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8 kg/m2) in a university research centre. Plasma was collected preprandially and for 180 min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180 min before an ad libitum lunch was provided.CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F (1,15)  = 14.737, p  < 0.01). Profiles of hunger/fullness did not differ between conditions (F (1,15)  = 0.505, p  = 0.488; F (1,15)  = 2.277, p  = 0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925 kJ; t (14)  = 0.201, p  = 0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size.These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.
Keywords: CCK; Satiety; Satiation; Eating behaviour; Appetite;

Glucagon like peptide-1 is an insulinotropic hormone released from intestinal L-cells in response to food ingestion. Here, we investigated mechanisms underlying the sensing of peptones by primary small intestinal L-cells. Meat, casein and vegetable-derived peptones (5 mg/ml), the L-amino acids Phe, Trp, Gln and Ala (20 mM each), and the dipeptide glycine-sarcosine (20 mM) stimulated GLP-1 secretion from primary cultures prepared from the small intestine. Further mechanistic studies were performed with meat peptone, and revealed the elevation of intracellular calcium in L-cells. Inhibition of the calcium sensing receptor (CaSR), transient receptor potential (TRP) channels and Q-type voltage gated calcium channels (VGCC) significantly attenuated peptone-stimulated GLP-1 release and reduced intracellular Ca2+ responses. CaSR inhibition also attenuated the GLP-1 secretory response to Gln. Targeting these pathways in L-cells could be used to increase endogenous production of GLP-1 and offer exploitable avenues for the development of therapeutics to treat diabetes and obesity.
Keywords: GLP-1; L-cell; Enteroendocrine; Peptones;

Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells by Catherine E. Moss; Leslie L. Glass; Eleftheria Diakogiannaki; Ramona Pais; Carol Lenaghan; David M. Smith; Marianne Wedin; Mohammad Bohlooly-Y; Fiona M. Gribble; Frank Reimann (16-20).
Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR119 agonism and assess the importance of GPR119 for the detection of ingested lipid.GLP-1 secretion was measured from murine primary cell cultures stimulated with a panel of GPR119 ligands. Plasma GLP-1 levels were measured in mice lacking GPR119 in proglucagon-expressing cells and controls after lipid gavage. Intracellular cAMP responses to GPR119 agonists were measured in single primary L-cells using transgenic mice expressing a cAMP FRET sensor driven by the proglucagon promoter.L-cell specific knockout of GPR119 dramatically decreased plasma GLP-1 levels after a lipid gavage. GPR119 ligands triggered GLP-1 secretion in a GPR119 dependent manner in primary epithelial cultures from the colon, but were less effective in the upper small intestine. GPR119 agonists elevated cAMP in ∼70% of colonic L-cells and 50% of small intestinal L-cells.GPR119 ligands strongly enhanced GLP-1 release from colonic cultures, reflecting the high proportion of colonic L-cells that exhibited cAMP responses to GPR119 agonists. Less GPR119-dependence could be demonstrated in the upper small intestine. In vivo, GPR119 in L-cells plays a key role in oral lipid-triggered GLP-1 secretion.
Keywords: GLP-1; GPR119; Incretin;

High fat diet impairs the function of glucagon-like peptide-1 producing L-cells by Paul Richards; Ramona Pais; Abdella M. Habib; Cheryl A. Brighton; Giles S.H. Yeo; Frank Reimann; Fiona M. Gribble (21-27).
Glucagon-like peptide-1 (GLP-1) acts as a satiety signal and enhances insulin release. This study examined how GLP-1 production from intestinal L-cells is modified by dietary changes.Transgenic mouse models were utilized in which L-cells could be purified by cell specific expression of a yellow fluorescent protein, Venus. Mice were fed on chow or 60% high fat diet (HFD) for 2 or 16 weeks. L-cells were purified by flow cytometry and analysed by microarray and quantitative RT-PCR. Enteroendocrine cell populations were examined by FACS analysis, and GLP-1 secretion was assessed in primary intestinal cultures.Two weeks HFD reduced the numbers of GLP-1 positive cells in the colon, and of GIP positive cells in the small intestine. Purified small intestinal L-cells showed major shifts in their gene expression profiles. In mice on HFD for 16 weeks, significant reductions were observed in the expression of L-cell specific genes, including those encoding gut hormones (Gip, Cck, Sct, Nts), prohormone processing enzymes (Pcsk1, Cpe), granins (Chgb, Scg2), nutrient sensing machinery (Slc5a1, Slc15a1, Abcc8, Gpr120) and enteroendocrine-specific transcription factors (Etv1, Isl1, Mlxipl, Nkx2.2 and Rfx6). A corresponding reduction in the GLP-1 secretory responsiveness to nutrient stimuli was observed in primary small intestinal cultures.Mice fed on HFD exhibited reduced expression in L-cells of many L-cell specific genes, suggesting an impairment of enteroendocrine cell function. Our results suggest that a western style diet may detrimentally affect the secretion of gut hormones and normal post-prandial signaling, which could impact on insulin secretion and satiety.
Keywords: GLP-1; Enteroendocrine; L-cell; High fat diet;

The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones by Claire L Meek; Hannah B Lewis; Frank Reimann; Fiona M Gribble; Adrian J Park (28-37).
Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role. The aim of this review is to summarise the effects of different bariatric surgery procedures upon gastrointestinal and pancreatic peptides, including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic hormone (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin, insulin, glucagon and somatostatin.
Keywords: Bariatric; Ghrelin; Gastrin; Cholecystokinin; Incretin; Oxyntomodulin;

The effect of encapsulated glutamine on gut peptide secretion in human volunteers by Claire L. Meek; Hannah B. Lewis; Bensi Vergese; Adrian Park; Frank Reimann; Fiona Gribble (38-46).
Weight loss and improved blood glucose control after bariatric surgery have been attributed in part to increased ileal nutrient delivery with enhanced release of glucagon-like peptide 1 (GLP-1). Non-surgical strategies to manage obesity are required. The aim of the current study was to assess whether encapsulated glutamine, targeted to the ileum, could increase GLP-1 secretion, improve glucose tolerance or reduce meal size.A single-center, randomised, double blind, placebo-controlled, cross-over study was performed in 24 healthy volunteers and 8 patients with type 2 diabetes. Fasting participants received a single dose of encapsulated ileal-release glutamine (3.6 or 6.0 g) or placebo per visit with blood sampling at baseline and for 4 h thereafter. Glucose tolerance and meal size were studied using a 75 g oral glucose tolerance test and ad libitum meal respectively.In healthy volunteers, ingestion of 6.0 g glutamine was associated with increased GLP-1 concentrations after 90 min compared with placebo (mean 10.6 pg/ml vs 6.9 pg/ml, p  = 0.004), increased insulin concentrations after 90 min (mean 70.9 vs 48.5, p  = 0.048), and increased meal size at 120 min (mean 542 g eaten vs 481 g, p  = 0.008). Ingestion of 6.0 g glutamine was not associated with significant differences in GLP-1, glucose or insulin concentrations after a glucose tolerance test in healthy or type 2 diabetic participants.Single oral dosing of encapsulated glutamine did not provoke consistent increases in GLP-1 and insulin secretion and was not associated with beneficial metabolic effects in healthy volunteers or patients with type 2 diabetes.
Keywords: Glucagon-like peptide 1; Insulin; Nutrients; Incretin; Glutamine;

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from enteroendocrine cells in the intestine along with other gut hormones (PYY, CCK and neurotensin) shown to affect metabolism and/or appetite. The secretion of many gut hormones is highly increased after gastric bypass operations, which have turned out to be an effective therapy of not only obesity but also type 2 diabetes. These effects are likely to be due, at least in part, to increases in the secretion of these gut hormones (except GIP). Therefore, stimulation of the endogenous hormone represents an appealing therapeutic strategy, which has spurred an interest in understanding the regulation of gut hormone secretion and a search for particularly GLP-1 and PYY secretagogues.The secretion of the gut hormones is stimulated by oral intake of nutrients often including carbohydrate, protein and lipid. This review focuses on stimulators of gut hormone secretion, the mechanisms involved, and in particular models used to investigate secretion. A major break-through in this field was the development of methods to identify and isolate specific hormone producing cells, which allow detailed mapping of the expression profiles of these cells, whereas they are less suitable for physiological studies of secretion. Isolated perfused preparations of mouse and rat intestines have proven to be reliable models for dynamic hormone secretion and should be able to bridge the gap between the molecular details derived from the single cells to the integrated patterns observed in the intact animals.
Keywords: GLP-1; Gut hormones; Perfused rodent intestine;

Regulation of body fat mass by the gut microbiota: Possible mediation by the brain by Erik Schéle; Louise Grahnemo; Fredrik Anesten; Anna Hallén; Fredrik Bäckhed; John-Olov Jansson (54-59).
New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further.
Keywords: Obesity; Gut microbiota; BDNF; GLP-1;

Hypothalamic inflammation and food intake regulation during chronic illness by J.T Dwarkasing; D.L. Marks; R.F Witkamp; K. van Norren (60-66).
Anorexia is a common symptom in chronic illness. It contributes to malnutrition and strongly affects survival and quality of life. A common denominator of many chronic diseases is an elevated inflammatory status, which is considered to play a pivotal role in the failure of food-intake regulating systems in the hypothalamus. In this review, we summarize findings on the role of hypothalamic inflammation on food intake regulation involving hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC). Furthermore, we outline the role of serotonin in the inability of these peptide based food-intake regulating systems to respond and adapt to changes in energy metabolism during chronic disease.
Keywords: Anorexia; Inflammation; Hypothalamus; Serotonin; NPY; Melanocortins;