Clinicopathologic features and diagnostic challenges of small cluster pattern appendiceal neuroendocrine tumors.

Appendiceal neuroendocrine neoplasms (NENs) can present with various growth patterns including the traditional triad of histologic patterns-insular, trabecular and tubular. A small cluster pattern was also found in this study and the literature on this specific morphology is limited. In this study, we conducted a comprehensive review of appendiceal NENs from our institution over a ten-year period. Clinical and demographic data were obtained from medical records. Immunohistochemical stains were performed with antibodies specific for synaptophysin, chromogranin, INSM1, CD56, serotonin and peptide YY. The small cluster pattern was found in 29.4 % of all cases evaluated. The tumor cells in these cases were predominantly located at the distal tip of the appendix, associated with fibrous obliteration. These tumors were smaller in size and tended towards less advanced tumor stage, with reduced incidence of lymphovascular and/or perineural invasion. Chromogranin expression was identified in 76 % of these cases. There is a heterogeneous hormone profile with 46.7 % serotonin and 33.3 % peptide YY. In conclusion, the small cluster pattern NENs present with unique histological features and hormone expression profile. Among the various neuroendocrine markers, INSM1 showed superior diagnostic performance, with high sensitivity and minimal non-specific staining.

The postprandial secretion of peptide YY1-36 and 3-36 in obesity is differentially increased after gastric bypass versus sleeve gastrectomy.

OBJECTIVES: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1-36 and PYY3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1-36 and PYY3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY1-36 and PYY3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. DESIGN AND SUBJECTS: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1-36 and PYY3-36 concentrations. RESULTS: Presurgery, the fasting and postprandial levels of PYY1-36 and PYY3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1-36 and PYY3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. CONCLUSIONS: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1-36 and PYY3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery.

Protein Source Influences Acute Appetite and Satiety but Not Subsequent Food Intake in Healthy Adults.

BACKGROUND: Although current recommendations encourage plant-based dietary patterns, data is limited as to whether the equivalent substitution of animal-based protein-rich foods with plant-based versions impacts ingestive behavior. OBJECTIVES: To compare higher-protein preloads, varying in protein source, on appetite, satiety, and subsequent energy intake. METHODS: Thirty-two adults (age: 25 ± 1 y; body mass index (BMI) measured in kg/m2: 24.2 ± 0.5 kg/m2) randomly consumed 250 kcal, protein-preload beverages (24 g protein), varying in protein source [whey, soy, and pea protein isolates (WHEY, SOY, and PEA) or micellar casein (CAS)] each morning for 3 acclimation days/preload. On day 4, participants completed a 4-h clinical testing day in which the respective preload was consumed, followed by blood sampling and questionnaires every 30 min for appetite and satiety. In addition, an ad libitum lunch was provided 4-h postpreload. On day 5, participants consumed the respective preload at home, followed by an ad libitum breakfast 30 min afterward. For normally-distributed data, repeated-measures analysis of variance (ANOVA) or Friedman nonparametric test were utilized to compare the main effects of protein source on study outcomes. Post hoc pairwise comparisons using least-significant differences (LSD) were then performed. RESULTS: CAS (-3330 ± 690 mm∗240 min) and PEA (-2840 ± 930mm∗240 min) reduced 4-h appetite compared with SOY (-1440 ± 936 mm∗240 min; both, P < 0.05). WHEY was not different (-2290 ± 930 mm∗240 min). CAS (3520 ± 84 pg/mL∗240 min) and PEA (3860 ± 864 pg/mL∗240 min) increased 4-h peptide YY concentrations compared with SOY (2200 ± 869 pg/mL∗240 min; both, P < 0.05). WHEY was not different (3870 ± 932 pg/mL∗240 min). No differences in ad libitum energy intake were observed. CONCLUSIONS: CAS and PEA, but not WHEY, elicited greater acute changes in appetite and satiety compared with SOY in healthy adults, supporting that not all protein sources are equivalent. This trial is registered at clinicaltrials.gov (NCT03154606).

The impacts and mechanisms of dietary proteins on glucose homeostasis and food intake: a pivotal role of gut hormones.

Glucose and energy metabolism disorders are the main reasons induced type 2 diabetes (T2D) and obesity. Besides providing energy, dietary nutrients could regulate glucose homeostasis and food intake via intestinal nutrient sensing induced gut hormone secretion. However, reviews regarding intestinal protein sensing are very limited, and no accurate information is available on their underlying mechanisms. Through intestinal protein sensing, dietary proteins regulate glucose homeostasis and food intake by secreting gut hormones, such as glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP). After activating the sensory receptors, such as calcium-sensing receptor (CaSR), peptide transporter-1 (PepT1), and taste 1 receptors (T1Rs), protein digests induced Ca2+ influx and thus triggered gut hormone release. Additionally, research models used to study intestinal protein sensing have been emphasized, especially several innovative models with excellent physiological relevance, such as co-culture cell models, intestinal organoids, and gut-on-a-chips. Lastly, protein-based dietary strategies that stimulate gut hormone secretion and inhibit gut hormone degradation are proposed for regulating glucose homeostasis and food intake.

Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies.

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.

A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans.

OBJECTIVE: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. DESIGN: GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. RESULTS: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. CONCLUSION: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.

Multiplexed Assay to Quantify the PP-Fold Family of Peptides in Human Plasma Using Microflow Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Peptide Tyr-Tyr (PYY1-36), pancreatic polypeptide (PP1-36) and neuropeptide Y (NPY1-36) constitute the PP-fold family of peptides that is involved in metabolic regulation. Very low plasma concentrations and cleavage into active 3-36 fragments challenge bioanalytical assays used for the quantification of these peptides. METHODS: We developed a multiplexed isotopic dilution assay to quantify PYY1-36, PP1-36, and NPY1-36 and their dipeptidyl peptidase-4 (DPP4)-derived metabolites PYY3-36, PP3-36 and NPY3-36. All peptides were immunocaptured from plasma using a monoclonal antibody and quantified by micro-ultra-HPLC-MS/MS. Blood samples from healthy volunteers were collected fasting and 30 min after nutrient stimulation. Method comparison was performed with commercial immunoassays. RESULTS: Linearity was shown in the measured intervals (r2 > 0.99). The lower limit of quantification (LLOQ) with a CV at 20% was 1.5 pM for PYY1-36 and PYY3-36, 3.0 pM for PP1-36 and PP3-36, 0.8 pM for NPY1-36 and 0.5 pM for NPY3-36. In all cases, intra- and inter-assay bias and imprecision were <21%. Pre-analytical stability required addition of a protease inhibitor cocktail. Physiological concentrations of PYY3-36, NPY3-36, PP1-36 and PP3-36 were above the LLOQ in 43% to 100% of the samples. PYY1-36 and NPY1-36 were above the LLOQ in 9% and 0% of the samples, respectively. Immunoassays showed higher concentrations of measurands and poor agreement when compared with micro-UHPLC-MS/MS. CONCLUSIONS: The assay allowed for specific multiplexed analysis of the PP-fold family of peptides and their DPP4-cleaved fragments in a single sample, thereby offering new perspectives to study the role and therapeutic potential of these essential peptide hormones in health and metabolic disease.

Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with delayed gastric emptying.

OBJECTIVE: People who are severely obese due to melanocortin-4 receptor (MC4R) deficiency experience hyperphagia and impaired fullness after a meal (satiety). Meal-induced satiety is influenced by hormones, such as peptide-YY (PYY), which are released by enteroendocrine cells upon nutrient delivery to the small intestine. DESIGN: We investigated whether gastric emptying and PYY levels are altered in MC4R deficiency. METHODS: Gastric emptying was measured with a gastric scintigraphy protocol using technetium-99m (99 Tcm )-Tin Colloid for 3.5 h in individuals with loss of function MC4R variants and a control group of similar age and weight. In a separate study, we measured plasma PYY levels before and at multiple time points after three standardised meals given to individuals with MC4R deficiency and controls. Fasting PYY (basal secretion) and postprandial PYY levels were measured and the area under the curve and inter-meal peak were calculated. RESULTS: We found that gastric emptying time was significantly delayed and percentage meal retention increased in individuals with MC4R deficiency compared to obese controls. In addition, fasting and mean PYY secretion throughout the day were decreased in MC4R deficiency, whereas postprandial PYY secretion was unaltered. CONCLUSION: Delayed gastric emptying and reduced basal PYY secretion may contribute to impaired satiety in people with obesity due to MC4R deficiency.

Beneficial metabolic effects of recurrent periods of beta-cell rest and stimulation using stable neuropeptide Y1 and glucagon-like peptide-1 receptor agonists.

AIM: To examine whether sequential administration of (d-Arg35 )-sea lamprey peptide tyrosine tyrosine (1-36) (SL-PYY) and the glucagon-like peptide-1 (GLP-1) mimetic, liraglutide, has beneficial effects in diabetes. METHODS: SL-PYY is an enzymatically stable neuropeptide Y1 receptor (NPY1R) agonist known to induce pancreatic beta-cell rest and improve overall beta-cell health. We employed SL-PYY and liraglutide to induce appropriate recurrent periods of beta-cell rest and stimulation, to assess therapeutic benefits in high fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. RESULTS: Previous studies confirm that, at a dose of 0.25 nmol/kg, liraglutide exerts bioactivity over an 8-12 hour period in mice. Initial pharmacokinetic analysis revealed that 75 nmol/kg SL-PYY yielded a similar plasma drug time profile. When SL-PYY (75 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 08:00 AM and 08:00 PM, respectively, to HFF-STZ mice for 28 days, reductions in energy intake, body weight, circulating glucose, insulin and glucagon were noted. Similarly positive, but slightly less striking, effects were also apparent with twice-daily liraglutide-only therapy. The sequential SL-PYY and liraglutide treatment also improved insulin sensitivity and glucose-induced insulin secretory responses, which was not apparent with liraglutide treatment, although benefits on glucose tolerance were mild. Interestingly, combined therapy also elevated pancreatic insulin, decreased pancreatic glucagon and enhanced the plasma insulin/glucagon ratio compared with liraglutide alone. This was not associated with an enhancement of beneficial changes in islet cell areas, proliferation or apoptosis compared with liraglutide alone, but the numbers of centrally stained glucagon-positive islet cells were reduced by sequential combination therapy. CONCLUSION: These data show that NPY1R-induced intervals of beta-cell rest, combined with GLP-1R-stimulated periods of beta-cell stimulation, should be further evaluated as an effective treatment option for obesity-driven forms of diabetes.

Targeting the Enteroendocrine System for Treatment of Obesity.

Mimetics of the anorexigenic gut hormone glucagon-like peptide 1 (GLP-1) were originally developed as insulinotropic anti-diabetic drugs but also evoke significant weight loss, leading to their recent approval as obesity therapeutics. Co-activation of receptors for GLP-1 and other gut hormones which reduce food intake - peptide YY (PYY3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) - is now being explored clinically to enhance efficacy. An alternative approach involves pharmacologically stimulating endogenous secretion of these hormones from enteroendocrine cells (EECs) to recapitulate the metabolic consequences of bariatric surgery, where highly elevated postprandial levels of GLP-1 and PYY3-36 are thought to contribute to improved glycaemia and weight loss.

The Enteroendocrine System in Obesity.

The enteroendocrine system coordinates the physiological response to food intake by regulating rates of digestion, nutrient absorption, insulin secretion, satiation and satiety. Gut hormones with important anorexigenic and/or insulinotropic roles include glucagon-like peptide 1 (GLP-1), peptide YY (PYY3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP). High BMI or obesogenic diets do not markedly disrupt this enteroendocrine system, which represents a critical target for inducing weight loss and treating co-morbidities in individuals with obesity.

Differences in gastrointestinal hormones and appetite ratings among obesity classes.

The aim of this study was to compare gastrointestinal (GI) hormones and subjective ratings of appetite among obesity classes, and between classes of obesity and controls. Ninety-eight adult individuals with obesity, divided into class I (n = 35), II (n = 44) and III (n = 19), together with 45 controls without obesity were included in this cross-sectional analysis. Body weight/composition, and basal and postprandial (after a 600 kcal fixed breakfast) plasma concentrations of acylated ghrelin, active glucagon-like peptide 1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK) and insulin, as well as subjective ratings of hunger, fullness, desire to eat (DTE) and prospective food consumption (PFC) were measured. There were no differences in the plasma concentration of GI hormones (either basal or postprandial) among obesity classes, except for insulin. In general, obesity was associated with impaired secretion of GI hormones. Ghrelin secretion did not decline postprandially in class-III obesity. GLP-1 peak for obesity class I and II was early and lower, while class III showed no postprandial GLP-1 response. Postprandial PYY response for obesity class II and III was absent, and class III showed a delayed and shortened postprandial CCK response. Obesity class II and III had greater basal insulin concentration compared to controls and postprandial insulin was greater in obesity class III versus class II, class I and controls. No differences were found for appetite ratings among obesity classes. In conclusion, obesity is characterized by impaired secretion of GI hormones, with reduced postprandial satiety, particularly in individuals with obesity class III. This abnormal pattern may lead to overeating.

GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon.

GLP1 produced in the upper part of the gut is released after food intake and acts by activating insulin secretion, but the role of GLP1 in the colon, where it is predominantly produced, remains unknown. Here we characterized the apical versus basolateral secretion of GLP1 and PYY and the paracrine mechanisms of action of these enterohormones in the human colon. We stimulated human colon tissue in different ex vivo models with meat peptone and we used immunofluorescence to study the presence of canonical and non-canonical receptors of GLP1. We found that PYY and GLP1 are secreted mainly at the gut lumen in unstimulated and stimulated conditions. We detected DPP4 activity and found that GLP1R and GCGR are widely expressed in the human colon epithelium. Unlike GLP1R, GCGR is not expressed in the lamina propria, but it is located in the crypts of Lieberkühn. We detected GLP1R expression in human colon cell culture models. We show that the apical secretion of PYY and GLP1 occurs in humans, and we provide evidence that GLP1 has a potential direct paracrine function through the expression of its receptors in the colon epithelium, opening new therapeutic perspectives in the use of enterohormones analogues in metabolic pathologies.

Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice.

Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.

Dissociable hormonal profiles for psychopathology and stress in anorexia and bulimia nervosa.

BACKGROUND: Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric conditions, in which both psychological and metabolic factors have been implicated. Critically, the experience of stress can precipitate loss-of-control eating in both conditions, suggesting an interplay between mental state and metabolic signaling. However, associations between psychological states, symptoms and metabolic processes in AN and BN have not been examined. METHODS: Eighty-five women (n = 22 AN binge/purge subtype, n = 33 BN, n = 30 controls) underwent remote salivary cortisol sampling and a 2-day, inpatient study session to examine the effect of stress on cortisol, gut hormones [acyl-ghrelin, peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1] and food consumption. Participants were randomized to either an acute stress induction or control task on each day, and plasma hormones were serially measured before a naturalistic, ad libitum meal. RESULTS: Cortisol-awakening response was augmented in AN but not in BN relative to controls, with body mass index explaining the most variance in post-awakening cortisol (36%). Acute stress increased acyl-ghrelin and PYY in AN compared to controls; however, stress did not alter gut hormone profiles in BN. Instead, a group-by-stress interaction showed nominally reduced cortisol reactivity in BN, but not in AN, compared to controls. Ad libitum consumption was lower in both patient groups and unaffected by stress. CONCLUSIONS: Findings extend previous reports of metabolic dysfunction in binge-eating disorders, identifying unique associations across disorders and under stress. Moreover, we observed disrupted homeostatic signaling in AN following psychological stress, which may explain, in part, the maintenance of dysregulated eating in this serious illness.

Amplifying the antidiabetic actions of glucagon-like peptide-1: Potential benefits of new adjunct therapies.

Clinically approved for the treatment of diabetes and obesity, glucagon-like peptide-1 (GLP-1) receptor agonists display prominent glucose- and weight-lowering effects as well as positive cardioprotective and neuroprotective actions. Despite these benefits, bariatric surgery remains superior in producing robust and sustained weight loss alongside improvements in metabolic control with possible diabetes remission. The current review considers the potential for adjunct therapies to augment the therapeutic actions of GLP-1 receptor agonists. In this regard, several gut-derived hormones also, modulated by bariatric surgery, display additive properties when combined with GLP-1 receptor agonists in both preclinical and clinical studies. In addition, glucocorticoids and oestrogen have shown promise in augmenting the biological actions of GLP-1 in animal models. Additionally, GLP-1 efficacy can also be enhanced by use of compounds that prolong GLP-1 receptor coupling to potentiate downstream receptor signalling. Taken together, therapies that activate GLP-1 receptor signalling, in combination with various other cell signalling pathways, show potential for treating type 2 diabetes and obesity with superiority over GLP-1 receptor agonist therapy alone.

Rational Development of Stable PYY3-36 Peptide Y2 Receptor Agonists.

PURPOSE: The anorectic effect of PYY3-36 makes it a potential pharmacological weight loss treatment. Modifications of the endogenous peptide to obtain commercially attractive pharmacological and biophysical stability properties are examined. METHODS: Half-life extended PYY3-36 analogues were prepared and examined regarding Y2-receptor potency as well as biophysical and stability properties. RESULTS: Deamidation of asparagine in position 18 and 29 was observed upon incubation at 37°C. Asparagine in position 18 - but not position 29 - could be substituted to glutamine without detrimental effects on Y2-receptor potency. Covalent dimers were formed via the phenol impurity benzoquinone reacting with two N-terminal residues (Isoleucine-Lysine). Both residues had to be modified to suppress dimerization, which could be done without negatively affecting Y2-receptor potency or other stability/biophysical properties. Introduction of half-life extending modifications in position 30 and 35 eliminated aggregation at 37°C without negatively affecting other stability properties. Placement of a protracting moiety (fatty acid) in the receptor-binding C-terminal region reduced Y2-receptor potency substantially, whereas only minor effects of protractor position were observed on structural, biophysical or stability properties. Lipidated PYY3-36 analogues formed oligomers of various sizes depending on primary structure and solution conditions. CONCLUSIONS: By rational design, a chemically and physically stable Y2-receptor selective, half-life extended PYY3-36 peptide has been developed.

Selective stimulation of colonic L cells improves metabolic outcomes in mice.

AIMS/HYPOTHESIS: Insulin-like peptide-5 (INSL5) is found only in distal colonic L cells, which co-express glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). GLP-1 is a well-known insulin secretagogue, and GLP-1 and PYY are anorexigenic, whereas INSL5 is considered orexigenic. We aimed to clarify the metabolic impact of selective stimulation of distal colonic L cells in mice. METHODS: Insl5 promoter-driven expression of Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) was employed to activate distal colonic L cells (LdistalDq). IPGTT and food intake were assessed with and without DREADD activation. RESULTS: LdistalDq cell stimulation with clozapine N-oxide (CNO; 0.3 mg/kg i.p.) increased plasma GLP-1 and PYY (2.67- and 3.31-fold, respectively); INSL5 was not measurable in plasma but was co-secreted with GLP-1 and PYY in vitro. IPGTT (2 g/kg body weight) revealed significantly improved glucose tolerance following CNO injection. CNO-treated mice also exhibited reduced food intake and body weight after 24 h, and increased defecation, the latter being sensitive to 5-hydroxytryptamine (5-HT) receptor 3 inhibition. Pre-treatment with a GLP1 receptor-blocking antibody neutralised the CNO-dependent improvement in glucose tolerance but did not affect the reduction in food intake, and an independent group of animals pair-fed to the CNO-treatment group demonstrated attenuated weight loss. Pre-treatment with JNJ-31020028, a neuropeptide Y receptor type 2 antagonist, abolished the CNO-dependent effect on food intake. Assessment of whole body physiology in metabolic cages revealed LdistalDq cell stimulation increased energy expenditure and increased activity. Acute CNO-induced food intake and glucose homeostasis outcomes were maintained after 2 weeks on a high-fat diet. CONCLUSIONS/INTERPRETATION: This proof-of-concept study demonstrates that selective distal colonic L cell stimulation has beneficial metabolic outcomes. Graphical abstract.

Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation.

The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic ß-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.

Gastrointestinal Peptides as Therapeutic Targets to Mitigate Obesity and Metabolic Syndrome.

PURPOSE OF REVIEW: Obesity affects over than 600 million adults worldwide resulting in multi-organ complications and major socioeconomic impact. The purpose of this review is to summarise the physiological effects as well as the therapeutic implications of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP) in the treatment of obesity and type 2 diabetes. RECENT FINDINGS: Clinical trials have proven that the widely used GLP-1 analogues have pleotropic effects beyond those on weight and glucose metabolism and appear to confer favourable cardiovascular and renal outcomes. However, GLP-1 analogues alone do not deliver sufficient efficacy for the treatment of obesity, being limited by their dose-dependent gastrointestinal side effects. Novel dual agonists for GLP-1/glucagon and GLP-1/GIP are being developed by the pharmaceutical industry and have demonstrated some promising results for weight loss and improvement in glycaemia over and above GLP-1 analogues. Triagonists (for example GLP-1/GIP/glucagon) are currently in pre-clinical or early clinical development. Gastrointestinal hormones possess complementary effects on appetite, energy expenditure, and glucose metabolism. We highlight the idea that combinations of these hormones may represent the way forward in obesity and diabetes therapeutics.