vasoactive-intestinal-peptide and Obesity

Topics: Cholecystokinin; Diabetes Mellitus, Type 2; Digestive System Physiological Phenomena; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Motilin; Neurotensin; Obesity; Pancreatic Polypeptide; Pentagastrin; Secretin; Somatostatin; Vasoactive Intestinal Peptide

The prefrontal cortex controls food reward seeking and ingestion, playing important roles in directing attention, regulating motivation towards reward pursuit, and the assignment of reward salience and value. The cell types that mediate these behavioral functions, however, are not well described. We report here that optogenetic activation of vasoactive peptide expressing (VIP) interneurons in both the infralimbic (IL) and prelimbic (PL) divisions of the medial prefrontal cortex in mice is sufficient to reduce acute, binge-like intake of high calorie palatable food in the absence of any effect on low calorie rodent chow intake in the sated animal. In addition, we discovered that the behavioral mechanisms associated with these changes in feeding differed between animals that underwent either IL or PL VIPergic stimulation. While IL VIP neurons showed the ability to reduce palatable food intake, this effect was dependent upon the novelty and relative value of the food source. In addition, IL VIP neuron activation significantly reduced novel object- and novel social investigative behavior. Activation of PL VIP neurons, however, produced a reduction in high calorie palatable food intake that was independent of food novelty. Neither IL nor PL VIP excitation changed motivation to obtain food reward. Our data show how neurochemically-defined populations of cortical interneurons can regulate specific aspects of food reward-driven behavior, resulting in a selective reduction in intake of highly valued food.

Topics: Animals; Behavior, Animal; Cognition; Eating; Food; Homeostasis; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Optogenetics; Prefrontal Cortex; Reward; Vasoactive Intestinal Peptide

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ-induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Gene Transfer Techniques; Glucose; Glucose Intolerance; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lentivirus; Mice; Mice, Inbred C57BL; Obesity; Vasoactive Intestinal Peptide

Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver-brain-pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote β-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in β-cells selectively, thereby efficiently promoting β-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic β-cells.

Topics: Animals; Blood Glucose; Brain; Carbachol; Cell Proliferation; Cholinergic Agonists; Forkhead Box Protein M1; Gastrointestinal Agents; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Liver; Mice; Neurons; Neurotransmitter Agents; Obesity; Pituitary Adenylate Cyclase-Activating Polypeptide; Signal Transduction; Vagotomy; Vagus Nerve; Vasoactive Intestinal Peptide

The prevalence of obesity has increased at alarming rates, particularly because of the increased consumption of high-fat diets (HFDs). The influence of HFDs on intrinsic innervation and the intestinal wall has not been fully characterized. The aim of this study was to investigate the morpho-quantitative aspects of myenteric neurons and the wall of the small intestine in mice fed a HFD.. Swiss mice were fed a HFD (59% kcal from fat) or standard chow (9% Kcal from fat) for 8 weeks. Segments of the duodenum, jejunum, and ileum were subjected to histological processing for morpho-quantitative examination of the intestinal wall and mucosal cells, and immunohistochemistry was performed to evaluate myenteric neurons. The data for each segment were compared between the groups using an unpaired Student's t-test or an equivalent nonparametric test.. The HFD increased body weight and visceral fat and decreased the length of the small intestine and the circumference of the ileum. In the duodenum, the HFD increased the density of the nitrergic subpopulation and decreased the area of nitrergic neurons and vasoactive intestinal peptide (VIP) varicosities. In the jejunum, the density of the nitrergic subpopulation was increased and the neuronal areas of the general population, nitrergic subpopulation and (VIP) varicosities were reduced. In the ileum, the density of the general population and nitrergic subpopulation were increased and the neuronal areas of the general population, nitrergic subpopulation and (VIP) varicosities were reduced. The morphometric parameters of the villi, crypts, muscular layer and total wall generally increased in the duodenum and jejunum and decreased in the ileum. In the duodenum and jejunum, the HFD promoted a decreased in the proportion of intraepithelial lymphocytes. In the ileum, the proportion of intraepithelial lymphocytes and goblet cells reduced, and the enteroendocrine cells increased.. The high-fat diet induces changes in the myenteric innervation of the small intestine, intestinal wall and mucosal cells responsible for the secretion of hormones and maintenance of the protective intestinal barrier. The morpho-quantitative data provide a basis for further studies to clarify the influence of HFD in the motility, digestive and absorptive capacity, and intestinal barrier.

Topics: Animals; Cell Proliferation; Diet, High-Fat; Duodenum; Enteroendocrine Cells; Goblet Cells; Ileum; Intestinal Mucosa; Intestine, Small; Jejunum; Lymphocyte Count; Male; Mice; Myenteric Plexus; Myosin Type V; Neurons; Nitrergic Neurons; Obesity; Vasoactive Intestinal Peptide

Y-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r(-/-)) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r(-/-) mice have low lean mass with increased adiposity. Npy6r(-/-) mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r(-/-), mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r(-/-), mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition.

Topics: Adiposity; Animals; Body Weight; Corticosterone; Diet; Energy Metabolism; Feeding Behavior; Fertility; Homeostasis; Insulin-Like Growth Factor I; Ligands; Mice; Mice, Inbred C57BL; Obesity; Pancreatic Polypeptide; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide Y; Signal Transduction; Suprachiasmatic Nucleus; Thinness; Vasoactive Intestinal Peptide

Obesity and type 2 diabetes are increasing in prevalence at an alarming rate in developed and developing nations and over 50% of patients with prolonged stages of disease experience forms of autonomic neuropathy. These patients have symptoms indicating disrupted enteric nervous system function including gastric discomfort, gastroparesis and intestinal dysmotility. Previous assessments have examined enteric neuronal injury within either type 1 diabetic or transgenic type 2 diabetic context. This study aims to assess damage to myenteric neurons within the duodenum of high-fat diet ingesting mice experiencing symptoms of type 2 diabetes, as this disease context is most parallel to the human condition and disrupted duodenal motility underlies negative gastrointestinal symptoms. Mice fed a high-fat diet developed symptoms of obesity and diabetes by 4 weeks. After 8 weeks, the total number of duodenal myenteric neurons and the synaptophysin density index were reduced and transmission electron microscopy showed axonal swelling and loss of neurofilaments and microtubules, suggesting compromised neuronal health. High-fat diet ingestion correlated with a loss of neurons expressing VIP and nNOS but did not affect the expression of ChAT, substance P, calbindin and CGRP. These results correlate high-fat diet ingestion, obesity and type 2 diabetes symptoms with a loss of duodenal neurons, biasing towards those with inhibitory nature. This pathology may underlie dysmotility and other negative GI symptoms experienced by human type 2 diabetic and obese patients.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Duodenum; Mice; Mice, Inbred C57BL; Mice, Obese; Myenteric Plexus; Neurons; Nitric Oxide Synthase; Obesity; Substance P; Vasoactive Intestinal Peptide

Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), β-endorphin-like immunoreactivity (β-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.

Topics: Adiposis Dolorosa; Humans; Neuropeptide Y; Neuropeptides; Obesity; Substance P; Vasoactive Intestinal Peptide

Recent genome-wide association (GWA) studies have identified a number of novel genes/variants predisposing to obesity. However, most GWA studies have focused on individual single-nucleotide polymorphism (SNPs)/genes with a strong statistical association with a phenotypic trait without considering potential biological interplay of the tested genes. In this study, we performed biological pathway-based GWA analysis for BMI and body fat mass. We used individual level genotype data generated from 1,000 unrelated US whites that were genotyped for ~500,000 SNPs. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm. A total of 963 pathways extracted from the BioCarta, Kyoto Encyclopedia of Genes and Genomes (KEGG), Ambion GeneAssist, and Gene Ontology (GO) databases were analyzed. Among all of the pathways analyzed, the vasoactive intestinal peptide (VIP) pathway was most strongly associated with fat mass (nominal P = 0.0009) and was the third most strongly associated pathway with BMI (nominal P = 0.0006). After multiple testing correction, the VIP pathway achieved false-discovery rate (FDR) q values of 0.042 and 0.120 for fat mass and BMI, respectively. Our study is the first to demonstrate that the VIP pathway may play an important role in development of obesity. The study also highlights the importance of pathway-based GWA analysis in identification of additional genes/variants for complex human diseases.

Topics: Adipose Tissue; Adult; Aged; Body Mass Index; Databases, Factual; Female; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Signal Transduction; United States; Vasoactive Intestinal Peptide; White People

It was hypothesized that the VPAC1 agonist may exert anti-obesity functions because VPAC1 is involved in the anorexigenic effects and the anti-inflammatory function of pituitary adenylate cyclase-activating polypeptide (PACAP)/vasoactive intestinal polypeptide (VIP). Furthermore, our in vitro test showed that the expression of VPAC1 increased significantly after the 3T3-L1 adipocytes were differentiated, and that incubation of adipocytes with VPAC1 agonist (10-1 000 nmol/L per 1x10(6) cells) resulted in stimulation of lipolysis. To test the effect of VPAC1 agonist [Lys15, Arg16, Leu27]-VIP (1-7) GRF (8-27) on diet-induced obesity (DIO), we further designed the following two in vivo experiments: (1) Mice were fed on high-fat diet (HFD) and intraperitoneally (i.p.) treated with VPAC1 agonist simultaneously for 28 d; (2) Mice were given HFD for 35 d, and subsequently fed on the same HFD and i.p. treated with VPAC1 agonist for the next 28 d. The physiological indices, including body weight, weight of white adipose tissue, plasma glucose and blood lipid, were collected. The results showed that treatment with VPAC1 agonist inhibited ingestion significantly and prevented the elevations in body weight and the weights of the white adipose tissues (epididymal and dorsal) induced by HFD. The increases in plasma glucose, cholesterol, triglycerides and LDL induced by HFD were also down-regulated in mice treated with VPAC1 agonist. VPAC1 agonist treatment also improved the glucose tolerance. Therefore, VPAC1 agonist treatment inhibits the development of the obesity induced by HFD and helps to improve the morbidities associated with DIO.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Body Weight; Diet, High-Fat; Mice; Obesity; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide

Based on findings in rodents, we sought to test the hypothesis that purinergic modulation of synaptic transmission occurs in the human intestine. Time series analysis of intraneuronal free Ca(2+) levels in submucosal plexus (SMP) from Roux-en-Y specimens was done using Zeiss LSM laser-scanning confocal fluo-4 AM Ca(2+) imaging. A 3-s fiber tract stimulation (FTS) was used to elicit a synaptic Ca(2+) response. Short-circuit current (I(sc) = chloride secretion) was recorded in mucosa-SMP in flux chambers. A distension reflex or electrical field stimulation was used to study I(sc) responses. Ca(2+) imaging was done in 1,222 neurons responding to high-K(+) depolarization from 61 surgical cases. FTS evoked synaptic Ca(2+) responses in 62% of recorded neurons. FTS caused frequency-dependent Ca(2+) responses (0.1-100 Hz). FTS Ca(2+) responses were inhibited by Omega-conotoxin (70%), hexamethonium (50%), TTX, high Mg(2+)/low Ca(2+) (< or = 100%), or capsaicin (25%). A P2Y(1) receptor (P2Y(1)R) antagonist, MRS-2179 or PLC inhibitor U-73122, blocked FTS responses (75-90%). P2Y(1)R-immunoreactivity occurred in 39% of vasoactive intestinal peptide-positive neurons. The selective adenosine A(3) receptor (AdoA(3)R) agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (2-Cl-IBMECA) caused concentration- and frequency-dependent inhibition of FTS Ca(2+) responses (IC(50) = 8.5 x 10(-8) M). The AdoA(3)R antagonist MRS-1220 augmented such Ca(2+) responses; 2-Cl-IBMECA competed with MRS-1220. Knockdown of AdoA(1)R with 8-cyclopentyl-3-N-(3-{[3-(4-fluorosulphonyl)benzoyl]-oxy}-propyl)-1-N-propyl-xanthine did not prevent 2-Cl-IBMECA effects. MRS-1220 caused 31% augmentation of TTX-sensitive distension I(sc) responses. The SMP from Roux-en-Y patients is a suitable model to study synaptic transmission in human enteric nervous system (huENS). The P2Y(1)/Galphaq/PLC/inositol 1,3,5-trisphosphate/Ca(2+) signaling pathway, N-type Ca(2+) channels, nicotinic receptors, and extrinsic nerves contribute to neurotransmission in huENS. Inhibitory AdoA(3)R inhibit nucleotide or cholinergic transmission in the huENS.

Topics: Aniline Compounds; Calcium; Chloride Channels; Electric Stimulation; Enteric Nervous System; Fluorescent Dyes; Humans; Microscopy, Confocal; Nerve Fibers; Neurons; Obesity; Quinazolines; Receptors, Purinergic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Submucous Plexus; Synaptic Transmission; Triazoles; Type C Phospholipases; Vasoactive Intestinal Peptide; Xanthenes

To test the hypothesis that genital prolapse may be related to peripheral nerve abnormalities, we examined the changes occurring to peptide-containing nerve processes supplying the periurethral muscles in women with stress urinary incontinence associated with prolapse.. Thirty patients with genital prolapse and 10 age-matched control subjects entered the study. All patients were evaluated by urodynamic investigations. Ten of 30 patients had pure stress urinary incontinence; none of the control subjects was incontinent. During surgery, four biopsy samples were obtained from each woman from the periurethral and perirectal muscles. The muscle sections were processed for immunohistochemistry using specific antibodies to glial (S-100 protein) and general neuronal markers (neuron-specific enolase) and neuropeptides, including neuropeptide Y, vasoactive intestinal polypeptide, and substance P. The evaluation of immunolabeled nerves was based on a semiquantitative analysis that allowed for a four-point ordinate scale score.. S-100 and neuron-specific enolase immunoreactive nerve fibers, running either singly or in small bundles, along with a dense network of neural processes containing neuropeptide Y, vasoactive intestinal polypeptide, and substance P, were found throughout the connective tissue and striated muscle of the control specimens. In contrast, in the muscle specimens from those with genitourinary prolapse, both the density and the intensity of neuropeptide Y, vasoactive intestinal polypeptide, and substance P immunoreactive nerves were markedly reduced compared with the control specimens.. The evidence of a reduced peptide-containing nerve supply to the perineal muscles provides a morphologic basis suggesting that neural abnormalities contribute to the pathogenesis of genital prolapse and urinary incontinence.

Topics: Aged; Biomarkers; Biopsy; Birth Weight; Connective Tissue; Denervation; Female; Humans; Middle Aged; Models, Neurological; Muscle, Skeletal; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Parity; Pelvic Floor; Peripheral Nervous System Diseases; Phosphopyruvate Hydratase; Postmenopause; Rectum; S100 Proteins; Substance P; Urethra; Urinary Incontinence, Stress; Uterine Prolapse; Vasoactive Intestinal Peptide

Topics: Adolescent; Adult; Anorexia Nervosa; Case-Control Studies; Clonidine; Female; Gonadotropin-Releasing Hormone; Human Growth Hormone; Humans; Levodopa; Obesity; Prolactin; Somatostatin; Vasoactive Intestinal Peptide

1. Hypothalamic concentrations of nine peptides with experimental effects on energy balance were compared in obese (fa/fa) and lean (Fa/?) male Zucker rats. To determine whether any peptide differences between obese and lean rats might be due to the overweight condition per se, separate groups of obese rats were food-restricted to reduce their body weight to lean values. 2. Concentrations of neuromedin B, a bombesin-like peptide, in the central hypothalamus were significantly higher in obese than in lean rats. This difference was not affected in food-restricted obese rats. 3. Hypothalamic levels of neuropeptide Y, an extremely potent central appetite stimulant, were similar in lean and freely fed obese rats but central hypothalamic levels of neuropeptide Y rose significantly in food-restricted obese rats. 4. These findings suggest that disturbances in hypothalamic neuromedin B concentrations may be involved in the obesity syndrome of the fa/fa Zucker rat. Increased central hypothalamic levels of neuropeptide Y in food-restricted rats suggest that this peptide may help to defend body weight by stimulating eating after weight loss.

Topics: Animals; Bombesin; Calcitonin Gene-Related Peptide; Food Deprivation; Galanin; Hypothalamus; Hypothalamus, Middle; Neurokinin B; Neuropeptide Y; Neuropeptides; Neurotensin; Obesity; Peptides; Radioimmunoassay; Rats; Rats, Zucker; Somatostatin; Substance P; Vasoactive Intestinal Peptide

The presence of vasoactive intestinal peptide (VIP) in the hypothalamus, anterior pituitary, and hypophyseal portal blood strongly suggests that VIP might be involved in the regulation of pituitary hormone secretion. To elucidate the relationship between VIP and the adrenergic system and its role in the mechanism of disturbed prolactin (PRL) and growth hormone (GH) release in obesity, serum VIP, GH, and PRL concentrations in response to alpha 2-adrenergic receptor agonist-clonidine were measured. Serum VIP levels were dramatically lower in obese as compared with non-obese patients, whereas clonidine did not alter VIP and PRL concentrations in either obese or non-obese patients. However, the response of GH to clonidine injection was blunted in obese patients. These results demonstrate an inhibited release of VIP in obesity. Whether a marked decrease of VIP may play a role in the mechanism of a disturbed release of GH and PRL remains to be explained.

Topics: Adult; Clonidine; Growth Hormone; Humans; Middle Aged; Obesity; Prolactin; Receptors, Adrenergic, alpha; Vasoactive Intestinal Peptide

Ten obese and 10 control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Blood glucose, insulin, somatostatin (SLI) and vasoactive intestinal polypeptide (VIP) concentrations were determined before and 30, 60, 90, 120, 180 and 240 min after the start of the meal. Basal SLI levels in the obese (14.4 +/- 0.7 ng/l) were not significantly different from those in the controls (15.5 +/- 0.8 ng/l), whereas after the meal a blunted secretory response was recorded. Baseline plasma VIP levels were higher in the obese (29.7 +/- 1.5 ng/l) than in the control subjects (19.8 +/- 1.3 ng/l) and, similarly to the controls, were unaffected by meal ingestion. Data suggest that in the course of obesity an enhanced VIP secretion in association with a diminished SLI responsiveness to meals occurs.

Topics: Adult; Blood Glucose; Food; Humans; Insulin; Male; Middle Aged; Obesity; Somatostatin; Vasoactive Intestinal Peptide

The concentrations and contents of immunoreactive substance P (SP), neurokinin A (NKA), vasoactive intestinal polypeptide (VIP) and gastrin releasing peptide (GRP) were measured in acid-ethanol extracts of intestine (duodenum-jejunum-ileum) and pancreas of C57BL/KsJ diabetes-obese (db/db) mice, Aston obese-hyperglycaemic (ob/ob) mice, and their respective lean controls. The intestinal concentration of GRP and pancreatic concentrations of VIP and GRP were 36-57% lower in lean Aston mice than lean C57BL/KsJ mice, indicating the influence of genetic background in control mice. Intestinal concentrations of SP and NKA were reduced by 19-33% in the db/db and ob/ob mutants compared with their lean controls, but the intestinal contents of these peptides were normal or greater than normal due to intestinal hypertrophy of the mutant mice. The intestinal VIP concentration was not altered, but the content was increased by 87% and 25% respectively in db/db and ob/ob mice, whereas the intestinal GRP concentration was reduced by 51% in ob/ob mice. Pancreatic concentrations and contents of NKA, VIP and GRP were similar in lean and db/db C57BL/KsJ mice. However, pancreatic concentrations and contents of VIP and GRP were reduced by 51-55% in ob/ob mice compared with their lean controls. The sensitivity of the present assay did not permit accurate determination of the low pancreatic concentrations of SP. The results suggest that the spontaneous ob/ob and db/db syndromes of obesity and diabetes in mice are associated with reduced intestinal concentrations of SP and NKA. The ob/ob mouse also exhibited reductions of intestinal GRP and pancreatic GRP and VIP concentrations. These changes in regulatory peptides may relate to abnormalities of intestinal and possibly pancreatic function in obese and diabetic mutant mice.

Topics: Animals; Diabetes Mellitus; Gastrin-Releasing Peptide; Insulin; Insulin Secretion; Intestines; Mice; Mice, Inbred C57BL; Mice, Obese; Mutation; Neurokinin A; Neuropeptides; Obesity; Pancreas; Peptides; Substance P; Vasoactive Intestinal Peptide

To determine the role of vasoactive intestinal polypeptide (VIP) and prolactin (PRL) in digestion, plasma VIP and PRL levels were measured in healthy, non-obese and obese premenopausal women fed isocaloric breakfasts containing a high carbohydrate or a high fat-protein content. A significant increase in plasma VIP concentration occurred after a high fat-protein breakfast, the increase being independent of body mass index. Plasma PRL level was unaltered by breakfast. Results suggest that the release of VIP after a meal depends on a high fat concentration in the duodenum, which may then stimulate bicarbonate release and fat-stimulated release of cholecystokinin.

Topics: Adult; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Food; Humans; Middle Aged; Obesity; Prolactin; Vasoactive Intestinal Peptide

This study evaluated the effect of gastric bypass on the glucose, insulin, vasoactive intestinal peptide (VIP), neurotensin, and motilin response to orally administered glucose in eight morbidly obese patients before and after operation. Preoperatively, all eight patients remained asymptomatic during an oral glucose tolerance test, which showed glucose intolerance and hyperinsulinism. Plasma VIP, neurotensin, and motilin remained below detectable levels for the entire test. At three months following gastric bypass (21% weight loss), all eight patients became acutely ill during a repeated oral glucose tolerance test and had the following symptoms: facial flushing (eight patients), palpitations (eight patients), nausea (seven patients), abdominal fullness (seven patients), pallor (four patients), diaphoresis (two patients), vomiting (two patients), and diarrhea (two patients). Significant release of neurotensin occurred in seven patients while three patients had release of VIP, further implicating these two peptides as part of the pathophysiologic spectrum of the "dumping syndrome."

Topics: Adult; Blood Glucose; Dumping Syndrome; Female; Glucose Tolerance Test; Humans; Jejunum; Male; Neurotensin; Obesity; Postoperative Complications; Stomach; Vasoactive Intestinal Peptide

Hypersecretion of catecholamine primarily affecting adrenaline levels arose in a patient given a jejunoileal bypass for severe obesity. Apart from organic factors, including a hetero and/or orthotopic pheochromocytoma and the therapeutic effect of beta-blocking drugs, it is suggested that the pathogenesis of the patient's condition is based on a hypersecretion of VIP, as sometimes occurs in patients with short intestine/syndrome.

Topics: Adult; Catecholamines; Epinephrine; Humans; Hypertension; Jejunoileal Bypass; Male; Norepinephrine; Obesity; Pheochromocytoma; Starvation; Vasoactive Intestinal Peptide

Plasma concentrations of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) were measured after a meal consisting of 11 ml meat extract and 40 ml of 20% soya oil in 11 patients before and 3 months after gastroplasty for morbid obesity. Gastroplasty results in a small proximal pouch with a narrow stoma allowing delayed emptying into the distal pouch, and consequently postprandial distension of the proximal pouch. Postprandial plasma PP increased significantly (P less than 0.01) independent of gastroplasty. PP is therefore not involved in the early satiety after gastroplasty. Postprandial plasma VIP increased significantly from fasting levels both before and after gastroplasty (P less than 0.05). Only 10 min after a meal, the median value of VIP was significantly higher after than before gastroplasty (P less than 0.02) and may be caused by distension of the proximal pouch.

Topics: Adult; Eating; Female; Humans; Middle Aged; Obesity; Pancreatic Polypeptide; Stomach; Time Factors; Vasoactive Intestinal Peptide

Twenty-six patients who were more than 35 per cent above their ideal weight were examined before the introduction of a weight reduction programme. At the end of a three-month period, seven patients had lost more than 10 per cent of their body weight. These patients had significantly lower triglyceride levels, fasting gastric inhibitory polypeptide levels (GIP) and prolactin levels. Fasting vasoactive intestinal polypeptide levels (VIP) before commencing diet were raised in six of the 19 patients who subsequently did not lose weight whereas the seven patients who lost weight had normal VIP levels (X2 = 3.07, P less than 0.05). Patients with high VIP levels had higher triglyceride levels, higher mean C-terminal glucagon-like immunoreactivity (C-GLI) and higher post glucose infusion secretin levels. There was a significant correlation between triglycerides and VIP. The significance of abnormally high VIP levels in obesity and the inability of these patients to lose weight is discussed.

Topics: Adult; Cholesterol; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Insulin; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Obesity; Secretin; Triglycerides; Vasoactive Intestinal Peptide

The age-related development of the capacity of the cardiac adenylate cyclase system to be stimulated with secretin, vasoactive intestinal peptide (VIP), glucagon, the beta-adrenergic agonist isoproterenol, Gpp(NH)p, and NaF was compared in obese (fa/fa) Zucker rats and their lean (FA/?) littermates. The obese (fa/fa) Zucker rats tested developed postweaning obesity associated with marked hypertriglyceridemia, mild hyperglycemia, and hyperinsulinism. At 4 weeks, there was already a 57% reduction in secretin-VIP-stimulated adenylate cyclase activity in fa/fa rats. At 12 weeks, the secretin-VIP-stimulation was reduced by 77%, and glucagon- and isoproterenol-stimulations by 16-21%. At 45 weeks, secretin-VIP-stimulation was reduced by 91%, glucagon- and isoproterenol stimulations by 34-42%, and Gpp(NH)p- and NaF-stimulations by 16-23%. The reductions of isoproterenol-, Gpp(NH)p-, and NaF-stimulations were totally or partially reversed in 30-week old fa/fa animals submitted for 5 weeks to severe food restriction that almost normalized the altered blood parameters. In sharp contrast, food restriction imposed a further decrease in secretin-VIP- and glucagon-stimulated adenylate cyclase activities. This pattern of impaired secretin-VIP-stimulated adenylate cyclase activity appeared limited to cardiac membranes in obese animals as the responses of liver, brain and anterior pituitary adenylate cyclase activities to secretin and/or VIP were unaltered. These results suggest that secretin-VIP receptors coupled to adenylate cyclase were rapidly and specifically altered in the heart of fa/fa Zucker rats.

Topics: Adenylyl Cyclases; Age Factors; Animals; Disease Models, Animal; Enzyme Activation; Food Deprivation; Glucagon; Isoproterenol; Myocardium; Obesity; Rats; Receptors, Cell Surface; Secretin; Vasoactive Intestinal Peptide

A comparison of the metabolic and gastroentero-pancreatic hormonal responses of ten obese and eight lean subjects to 12 h and 36 h fasts has been made. Each subject was given a 50 g oral glucose tolerance test at the end of both 12 h and 36 h starvation. After the 12 h fast blood glucose and 3-hydroxybuty-rate were similar in each group but blood glycerol was 30% higher in the obese subjects. Plasma insulin and vaso-active intestinal polypeptide were also higher in the obese subjects after 12 h starvation. After 36 h starvation in the lean subjects blood glucose was unchanged but on refeeding with 50 g oral glucose, glucose tolerance was impaired. In the same group blood glycerol and 3-hydroxybutyrate rose after 36 h starvation. Plasma glucagon, secretin and vaso-active intestinal polypeptide rose after 36 h starvation in the lean subjects but plasma insulin was unchanged. Refeeding with oral glucose suppressed the increased plasma glucagon, secretin and vaso-active intestinal polypeptide. After the 36 h fast in the obese subjects, blood glucose was unchanged, blood glycerol fell, but blood 3-hydroxybutyrate rose although to a reduced level in comparison with the lean subjects. In the obese group there was no change in plasma glucagon, secretin or vaso-active intestinal polypeptide after 36 h starvation, although plasma insulin fell. The results show different metabolic and gastro-entero-pancreatic hormonal responses to fasting in lean and obese human subjects and suggest an important metabolic role of glucagon, secretin and vaso-active intestinal polypeptide during starvation.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; Fasting; Female; Gastrointestinal Hormones; Glucagon; Glycerol; Humans; Hydroxybutyrates; Insulin; Lipolysis; Male; Middle Aged; Obesity; Secretin; Vasoactive Intestinal Peptide

Topics: Animals; Appetite Regulation; Cholecystokinin; Endorphins; Enkephalins; Gastrointestinal Hormones; Glucagon; Humans; Mice; Obesity; Secretin; Vasoactive Intestinal Peptide