ceruletide and Obesity

Of the many factors that influence food intake, there is strong evidence that opioid and CCK peptides, which stimulate feeding and elicit satiety, respectively, are important components that may act in concert to regulate energy balance. Cholecystokinin peptides have been isolated in both the brain and gastrointestinal tract, and changes in concentration in the brain and in plasma have been shown to vary with feeding. Peripherally injected CCK has been shown to elicit satiety in many species, including humans, an effect that may be mediated in the CNS via the vagus. In several species, most notably the sheep, direct injection into the CSF potently decreases food intake. Questions remaining regarding the role of CCK peptides in eliciting satiety include the sites and mechanisms of action. It is unknown whether CCK acts directly on receptors, indirectly on some other parameter, or as a neurotransmitter. Although opioid peptides have also been localized in portions of both the periphery and brain, a specific physiological role for their presence has not yet been determined. Opioid peptides from three families--endorphins, enkephalins, and dynorphins--have been shown to stimulate feeding in various species. They have been active at several opioid receptor types in the CNS, but there is limited evidence to suggest they affect food intake when administered peripherally. In contrast, peripheral injection of opiate antagonists has effectively decreased food intake, an observation that led to the original hypothesis that opioids were involved in the hunger component in the control of food intake and that excess concentrations might be involved in the development of obesity. An increasing body of evidence supports the concept that opioid and CCK peptides may interact to control food intake, but the evidence is more suggestive than conclusive.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; beta-Endorphin; beta-Lipotropin; Brain; Ceruletide; Cholecystokinin; Digestive System Physiological Phenomena; Dynorphins; Eating; Endorphins; Enkephalins; Fasting; Food; Humans; Immunologic Techniques; Kinetics; Morphine; Nervous System; Neurons; Obesity; Peptide Fragments; Protein Precursors; Receptors, Cell Surface; Receptors, Cholecystokinin; Satiation; Sincalide; Species Specificity; Structure-Activity Relationship; Tissue Distribution

Since the mid-1970s, evidence has accumulated that cholecystokinin (CCK) has a role as a neuromodulator or neurotransmitter in the central nervous system as well as in the periphery. CCK has been shown to have a variety of effects on gastrointestinal functions and is one of the main candidates for a role as a peripheral negative feedback signal to stop feeding behavior. CCK produces satiety not only in animals but also in man: it reduces appetite and activation arising from the preparation of a meal and inhibits intake of liquid and solid food in both lean and obese subjects. The closely related peptide caerulein has similar effects. The site of action of peripherally administered CCK seems to be on an abdominal organ innervated by gastric vagal branches and relayed to the brain by afferent vagal fibres, since selective gastric vagotomy blocks the satiety effect, but pharmacological antagonism of vagal motor effects or lesions of the ventromedial hypothalamus do not. CCK also may have a role in the regulation of pain perception. In mice, CCK and caerulein were shown to produce a decrement in response to noxious stimulation after peripheral and central administration. In man, caerulein was demonstrated to relieve pain originating from biliary and renal colic as well as from cancer and ischemia. A series of studies in healthy man revealed that caerulein also alleviates experimentally induced cutaneous pain. Data from animal studies suggest that CCK-like peptides not only are able to produce analgesic effects on their own, but also are involved in the modulation of opioid systems mediating analgesia. Further study of these effects of CCK should elucidate the regulatory connections between the life-sustaining functions of feeding and pain sensation.

Topics: Analgesics; Animals; Appetite Depressants; Central Nervous System; Ceruletide; Cholecystokinin; Digestive System; Dogs; Endorphins; Feeding Behavior; Female; Gastrointestinal Motility; Haplorhini; Humans; Hunger; Male; Mice; Neural Pathways; Obesity; Pain; Rats; Satiety Response; Sincalide; Vagus Nerve

Intramuscular ceruletide or placebo was given in a randomized double-blind crossover design to 12 non-obese and 12 obese individuals, 30 min before a palatable lunch meal. No significant effects were found on the amount of food intake or the hunger ratings in any group. Although rapid CCK or ceruletide infusions have been found in some studies to reduce food intake in man and animals, slow infusions have increased food intake. Under the present study conditions, the moderate rate of release of ceruletide from intramuscular depots did not affect the food intake.

Topics: Adult; Ceruletide; Eating; Energy Intake; Female; Humans; Hunger; Injections, Intramuscular; Male; Middle Aged; Obesity; Satiation

Obesity is an important risk factor for severe acute pancreatitis. The necrosis of epididymal adipose tissue occurs in severe acute pancreatitis. Adipose tissue macrophages play an important role in metabolic related inflammation. Therefore, we explored the potential mechanisms between adipose tissue macrophages and obesity-related severe acute pancreatitis.. Severe acute pancreatitis mice model was induced by caerulein with lipopolysaccharide. The severity of severe acute pancreatitis was evaluated according to the morphological, general, and biochemical change. We assessed the injury of epididymal white adipose tissue, pancreas, and adipose tissue macrophages in obese mice and lean mice with severe acute pancreatitis. Outcomes of caerulein-induced severe acute pancreatitis were studied in lean and obese mice with or without lipase inhibitor orlistat.. Fat necrosis and pancreatic injury increased in the SAP groups. High levels of serum free fatty acid and triglyceride were increased significantly in the SAP group. The NLRP3-caspase1 inflammasome signal pathway in adipose tissue macrophages markedly enhanced in the SAP groups compared with control group. Free fatty acid can trigger macrophages inflammation through NLRP3-caspase1. Lipase inhibited by orlistat remarkably decreased in adipose tissue necrosis, and the levels of serum lipase, amylase, and pancreatic tissue damage decreased in the orlistat group compared with the SAP group. The NLRP3-caspase1 inflammasome pathway in adipose tissue macrophages markedly decreased in the orlistat groups compared with SAP group. The levels of serum free fatty acid and triglyceride were decreased significantly in the orlistat group.. Inflammation increases in adipose tissue macrophages of obese mice with severe acute pancreatitis. Free fatty acid generated via adipocyte lipolysis worsens inflammation in adipose tissue macrophages and the outcome of severe acute pancreatitis in obese mice through the NLRP3-caspase1 inflammasome pathway.

Topics: Acute Disease; Adipose Tissue; Animals; Caspase 1; Ceruletide; Fatty Acids, Nonesterified; Inflammasomes; Inflammation; Lipase; Macrophages; Mice; Necrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Orlistat; Pancreatitis; Triglycerides

Obesity is one of the most important risk factors for acute pancreatitis. Based on the effect of sleeve gastrectomy (SG) on improving body weight and blood lipids, we investigated whether SG is beneficial in improving pancreatitis in obese rats.. Two studies were used to evaluate the effect of SG on the first onset of pancreatitis and acute episodes of recurrent pancreatitis in obese rats. A high-fat diet (HFD) for 8 weeks resulted in obesity in rats. Study 1: Obese rats were treated with SG and sham surgery. Pancreatitis was induced by intraperitoneal injection of cerulein at 6 weeks after surgery. The severity of pancreatitis was assessed by histological examination, cytokines, and infiltration of inflammatory cells. Study 2 performed the same procedure as in study 1, except that rats were intraperitoneally injected with a small dose of cerulein three times a week for 6 weeks before surgery to induce recurrent pancreatitis.. The body weight, food intake, and blood lipids of SG rats in study 1 and study 2 were significantly lower than those of sham rats during the 6 weeks after surgery. Compared with sham rats, SG rats in both studies had fewer inflammatory cytokines, inflammatory cell infiltration, and pathological injury in the pancreas after cerulein-induced acute pancreatitis.. SG reduces the severity of the first onset of pancreatitis and the seriousness of acute episodes of recurrent pancreatitis. The improvement of lipid metabolism and body weight by SG may play an important role in this effect.

Topics: Acute Disease; Animals; Ceruletide; Gastrectomy; Obesity; Obesity, Morbid; Pancreatitis; Rats

Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ coactivator 1α (PGC-1α) is a transcriptional coactivator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were: (1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and (2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first; subsequently, wild-type and PGC-1α knockout (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly downregulated in pancreas of obese rats and mice versus lean animals. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Interleukin-6 (Il6) mRNA levels were dramatically upregulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild-type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild-type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild-type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild-type mice. PGC-1α KO mice with pancreatitis, but not wild-type mice, exhibited increased myeloperoxidase activity in the lungs, together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor glycoprotein 130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of nuclear factor-κB (NF-κB) towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated upregulation of Il6 in pancreas in pancreatitis, leading to a severe inflammatory response. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Animals; Ceruletide; Disease Models, Animal; Interleukin-6; Male; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Obesity; Pancreas; Pancreatitis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Rats, Zucker; Signal Transduction; Taurocholic Acid; Transcription Factor RelA; Up-Regulation

Acute pancreatitis is a substantial clinical problem accounting for 240,000 hospital admissions yearly in the United States. Obesity is epidemic and is clearly an independent risk factor for increased severity of acute pancreatitis (AP). Adipose tissue is an endocrine organ that secretes a variety of metabolically active substances termed adipokines. However, the role of adipokines in modulating acute pancreatitis severity remains incompletely understood. Dietary fish oil is rich in omega-3 free fatty acids and attenuates adipose tissue-induced inflammation. Therefore, we hypothesized that feeding obese mice diets rich in fish oil would alter the adipokine milieu and attenuate the severity of pancreatitis.. Lean (C57BL/6 J) and obese (LepDb) mice were fed either a soybean oil- or fish oil-rich diet for 4 weeks. AP was induced by six hourly intraperitoneal injections of cerulein (50 μg/kg). Serum adipokine levels were measured, and pancreatitis severity was assessed histologically and by measuring pancreatic concentrations of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), myleoperoxidase (MPO), and monocyte chemoattractant protein-1 (MCP-1).. Obese mice developed more severe pancreatitis than lean mice. Fish oil significantly decreased serum leptin (lean and obese) and increased serum adiponectin (lean only). Fish oil did not alter the baseline pancreatic inflammatory milieu, nor did it change histologic or biochemical pancreatitis severity.. These data demonstrate that a diet rich in fish oil altered the adipokine milieu in lean and congenitally obese mice; however, fish oil did not improve pancreatitis severity induced with cerulein hyperstimulation.

Topics: Adipokines; Adiponectin; Animals; Ceruletide; Chemokine CCL2; Dietary Fats, Unsaturated; Female; Fish Oils; Interleukin-1beta; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Obesity; Pancreatitis; Pancrelipase; Peroxidase; Severity of Illness Index; Soybean Oil

Obesity is an independent risk factor for severe acute pancreatitis, though the mechanisms underlying this association are unknown. The powerful anti-inflammatory adipokine adiponectin is decreased in obesity. We recently showed that the severity of pancreatitis in obese mice is inversely related to circulating adiponectin levels, and therefore hypothesized that adiponectin upregulation would attenuate the severity of pancreatitis in obese mice.. Forty congenitally obese mice were studied. Seven days prior to study, 20 mice received a single tail vein injection of adenovirus expressing recombinant murine adiponectin (APN; 2 × 10⁸ plaque forming unit (pfu)), and the remainder received a control adenoviral vector expressing β-galactosidase (β-gal; 2 × 10⁸ pfu). Half of the mice in each group had pancreatitis induced by cerulein injection (50 mcg/kg IP hourly for 6 h). The other half received saline on the same schedule. Serum APN concentration and pancreatic tissue concentrations of interleukin (IL)-6, IL-1β, and MCP-1 were measured by ELISA. Histologic pancreatitis score was calculated based on the degree of inflammation (0-4), edema (0-4), and vacuolization (0-4). Data were analyzed by ANOVA and Tukey's tests; p < 0.05 was considered significant.. No difference in body weight was observed between groups. Serum APN was significantly upregulated in the APN group compared with the β-gal group. Pancreatic tissue concentration of IL-6 was significantly decreased in the APN group compared with the β-gal group. No change either in pancreatic tissue concentration of IL-1β and MCP-1 or in the severity of histologic pancreatitis were observed.. Adiponectin upregulation modulates the pancreatic cytokine milieu but does not attenuate pancreatitis in this model of mild acute pancreatitis.

Topics: Adenoviridae; Adiponectin; Analysis of Variance; Animals; Ceruletide; Chemokine CCL2; DNA, Recombinant; Female; Genetic Vectors; Interleukin-1beta; Interleukin-6; Mice; Mice, Obese; Obesity; Pancreas; Pancreatitis; Up-Regulation

Obesity is a risk factor for acute pancreatitis (AP), but the molecular mechanism remains unclear. Adiponectin, an adipose tissue-derived secretory factor, has anti-inflammatory properties in addition to various biological functions, and its plasma concentrations are reduced in obese subjects. However, the role of adiponectin in AP has not been investigated.. To determine the effects of adiponectin on AP.. We investigated the effects of adiponectin on experimental AP by using adiponectin-knockout (APN-KO) mice and adenovirus-mediated adiponectin over-expression. AP was induced by 10 hourly intraperitoneal injections of low-dose caerulein (10 microg/kg) after 2 week feeding of normal chow or a high-fat diet (HFD) in wild-type (WT) and APN-KO mice. We evaluated the severity of AP biochemically and morphologically.. Low-dose caerulein treatment did not induce pancreatic damage in either WT or APN-KO mice under normal chow feeding. APN-KO mice, but not WT mice, fed a HFD and then treated with caerulein developed pancreatic damage and inflammation, accompanied by increased macrophage/neutrophil infiltration and upregulation of pro-inflammatory mediators such as tumour necrosis factor alpha in the pancreas. Adenovirus-mediated over-expression of adiponectin attenuated the severity of HFD/caerulein-induced AP in APN-KO mice.. Adiponectin plays a protective role in caerulein-induced AP in HFD-fed mice.

Topics: Acute Disease; Adiponectin; Adipose Tissue; Animals; Ceruletide; Dietary Fats; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pancreatitis; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index

The present study evaluates long-term effects of the CCK-agonist caerulein and the CCK-A antagonist loxiglumide in obese and lean Zucker rats. Caerulein and loxiglumide altered food intake neither in obese nor in lean rats. By as yet unknown mechanisms, however, weight increase was accelerated by loxiglumide and reduced by caerulein in obese and lean rats. Caerulein increased pancreatic weight only in lean but not in obese rats. Thus, obese rats show a resistance of pancreatic CCK-A receptors. The failure of CCK-agonist and -antagonist to alter food intake suggests that this CCK-resistance is not responsible for obesity in the genetically altered rats.

Topics: Animals; Body Weight; Ceruletide; Cholecystokinin; Drug Resistance; Eating; Female; Male; Obesity; Organ Size; Pancreas; Proglumide; Rats; Rats, Zucker; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiety Response

Clinical as well as experimental studies in insulinopenic diabetes mellitus have demonstrated abnormal pancreatic exocrine responses to cholecystokinin (CCK). In the present study, we examined pancreatic exocrine and endocrine function in the recently developed genetically diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and compared them with those in the control Long-Evans Tokushima Otsuka (LETO) rats of the same age. Stepwise increasing doses of CCK octapeptide (CCK-8; 0.027-7.0 nmol.kg-1.h-1) evoked a characteristic biphasic dose-response curve for pancreatic juice and protein output in the LETO rats, whereas the OLETF rats were totally insensitive to CCK-8 stimulation. However, the responsiveness and the sensitivity to both carbamylcholine and secretin were similar in the two groups. Intraduodenal infusion of casein (500 mg/h) failed to stimulate pancreatic exocrine secretion in the OLETF rats despite a greater CCK response than in the LETO rats (peak response: 8.43 +/- 0.97 vs 5.12 +/- 0.30 pmol/l in LETO, P < 0.01). Intravenous infusion of CCK-8 (4.4 nmol.kg-1.20 min-1) caused a significant increase in serum insulin concentrations and a concomitant decrease in glucose levels in the LETO rats but not in the OLETF rats. On the other hand, an intravenous bolus injection of 1.1 mmol/kg glucose caused a greater insulin release in the OLETF rats than in the LETO rats. In contrast, gastric acid secretion in the OLETF rats was significantly high in basal and in response to intravenous infusion of CCK-8 compared with that in the LETO rats. Four subcutaneous injections of 20 micrograms/kg caerulein at hourly intervals over 3 h induced acute pancreatitis in the LETO rats but did not elicit any significant increase in serum amylase or lipase activities and pancreatic wet weight or histological evidence of acute pancreatitis in the OLETF rats. These results indicate that the exocrine and endocrine pancreas of the recently developed genetically diabetic OLETF rats are totally and specifically insensitive to exogenous and endogenous CCK stimulation, whereas parietal cells in these rats are sensitive to CCK stimulation.

Topics: Acute Disease; Animals; Carbachol; Caseins; Ceruletide; Cholecystokinin; Duodenum; Gastric Acid; Glucose; Injections; Insulin; Islets of Langerhans; Male; Obesity; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Secretin; Sincalide

The secretory function of the exocrine pancreas has been studied in dispersed pancreatic acini from obese and homozygous lean Zucker rats at 6 and 22 wk. No abnormality was found in acini from young rats. Acini from 22 wk obese and lean rats were equally responsive to secretagogues which stimulate cAMP, i.e. vasoactive intestinal peptide (VIP) and secretin. By contrast, there was a reduction in the maximum responsiveness to caerulein and carbamylcholine in acini from obese rats. These latter secretagogues act through mobilization of intracellular Ca2+. Since obese animals are insulin resistant and amylase release is modulated by insulin, the role of insulin resistance in the secretory defect was then investigated. A group of 22 wk obese rats received treatment with Ciglitazone (a drug which reduces insulin resistance in obese laboratory animals) for 4 wk before the secretion study. Despite the expected reduction in insulin resistance there was no improvement of the secretory defect seen with caerulein and carbamylcholine stimulation. Thus, the secretory abnormality in the exocrine pancreas of adult obese Zucker rats does not appear to be directly associated with insulin resistance. Furthermore, the secretory defect is linked to those secretagogues which induce Ca2+-independent phosphoinositide hydrolysis and Ca2+ mobilization in the target cell.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Carbachol; Ceruletide; Female; Homozygote; In Vitro Techniques; Insulin; Kinetics; Obesity; Organ Size; Pancreas; Proteins; Rats; Rats, Zucker

Cholecystokinin (CCK) has been shown to produce satiety not only in a variety of animal species but in man as well. In healthy humans, CCK reduces appetite and activation arising from the preparation of a meal, inhibits intake of liquid food in both non-obese and obese subjects, and decreases the intake of solid food. The closely related caerulein produces a similar reduction of solid food consumption in lean and, as suggested by preliminary results, in obese man. There is good evidence that the satiety effect of CCK depends on its inhibition of gastric emptying and the consequent gastric distension. In healthy man, the same dose of caerulein found to reduce food intake also slows gastric emptying of a semisolid meal. This effect seems to be relayed into the brain by afferent vagal fibers as in animals; selective gastric vagotomy blocks the satiety effect while pharmacological antagonism of vagal motor effects or lesions in the ventro-medial hypothalamus do not. Ongoing studies suggest that gastric vagotomy also blocks the satiety effects of caerulein in man. A critical role for CCK in the control of human feeding behavior seems certain.

Topics: Ceruletide; Cholecystokinin; Electroencephalography; Feeding Behavior; Female; Gastric Emptying; Humans; Male; Obesity; Psychomotor Performance; Satiation; Vagotomy

Congenitally obese mice are hyperphagic, suggesting that their obesity is secondary to defects in normal satiety mechanisms. The present study compares the effects of caerulein, bombesin, and pancreatic polypeptide (three equimolar doses each of 3, 9, and 27 nmol/kg) on food intake in 10 pairs of lean and obese mice. After the intraperitoneal injection of saline, obese mice eat 240% more of a liquid meal (Magnacal) than their lean littermates (P less than 0.01). All three doses of caerulein significantly inhibited food intake in both obese and lean mice. Although the highest dose of bombesin significantly decreased food intake in both obese and lean mice, the lowest dose was only effective in obese mice. In contrast, none of these doses of pancreatic polypeptide had a significant effect on food intake in either lean or obese mice. A dose of bovine pancreatic polypeptide of 200 nmol/kg was required to significantly reduce food intake in lean and obese mice. This study demonstrates that obese mice respond to satiety signals and may even be more sensitive than their lean littermates to some messengers. In addition, the previously described reversal of this obesity syndrome by pancreatic polypeptide in doses of approximately 2.5 and 25 nmol X kg-1 X day-1 is unlikely to be due to effects of this peptide on food intake.

Topics: Animals; Bombesin; Ceruletide; Depression, Chemical; Eating; Female; Mice; Mice, Obese; Obesity; Pancreatic Polypeptide; Peptides; Satiation