A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice.

BACKGROUND: There are no drugs on the market that can reverse or slow Alzheimer's disease (AD) progression. A protease-resistant Cholecystokinin (CCK) analogue used in this study is based on the basic structure of CCK, which further increases the stability of the peptide fragment and prolongs its half-life in vivo. We observed a neuroprotective effect of CCK-8L in APPswe/PS1dE9 (APP/PS1) AD mice. However, its corresponding mechanisms still need to be elucidated. OBJECTIVE: This study examined CCK-8L's neuroprotective effects in enhancing cognitive impairment by regulating mitochondrial dynamics through AMPK/Drp1 pathway in the APP/PS1 AD mice. METHODS: Behavioural tests are applied to assess competence in cognitive functions. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria of hippocampal neurons, Immunofluorescent staining was employed to assay for Aß1-42, APP, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and dynamin-related protein1 (Drp1). CRISPR/Cas9 was utilized for targeted knockout of the CCKB receptor (CCKBR) in the mouse APP/PS1 hippocampal CA1 region. A model of lentiviral vector-mediated overexpression of APP in N2a cells was constructed. RESULTS: In vivo, experiments revealed that CCK analogue and liraglutide significantly alleviated cognitive deficits in APP/PS1 mice, reduced Aß1-42 expression, and ameliorated l damage, which is associated with CCKBR activation in the hippocampal CA1 region of mice. In vitro tests showed that CCK inhibited mitochondrial fission and promoted fusion through AMPK/Drp1 pathway. CONCLUSIONS: CCK analogue ameliorates cognitive deficits and regulates mitochondrial dynamics by activating the CCKB receptor and the AMPK/Drp1 pathway in AD mice.

Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.

[Effects of metabolic surgery on islet function in Asian patients with type 2 diabetes].

Type 2 diabetes is a high-profile global public health problem, particularly in Asia. The young age of onset, low body mass index, and early appearance of pancreatic islet dysfunction are characteristics of Asian patients with T2DM. Metabolic surgery has become the standard treatment for T2DM patients and can significantly improve T2DM through a variety of mechanisms including modulation of energy homeostasis and reduction of body fat mass. Indeed, restoration of islet function also plays an integral role in the remission of T2DM. After metabolic surgery, islet function in Asian T2DM patients has improved significantly, with proven short-term and long-term effects. In addition, islet function is an important criterion and reference for patient selection prior to metabolic surgery. The mechanism of islet function improvement after metabolic surgery is not clear, but postoperative anatomical changes in the gastrointestinal tract leading to a number of hormonal changes seem to be the potential cause, including glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, ghrelin, and cholecystokinin. The authors analyzed the current retrospective and prospective studies on the effect of metabolic surgery on the islet function of Asian T2DM patients with a low BMI and its mechanism, summarized the clinical evidence that metabolic surgery improved islet function in Asian T2DM patients with a low BMI, and discussed its underlying mechanism. It is of great significance for realizing personalized and precise treatment of metabolic surgery and further improving its clinical benefits.

Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.

Obesity has become a prevailing health burden globally and particularly in the US. It is associated with many health problems, including cardiovascular disease, diabetes and poorer mental health. Hence, there is a high demand to find safe and effective therapeutics for sustainable weight loss. Cholecystokinin (CCK) has been implicated as one of the first gastrointestinal hormones to reduce overeating and suppress appetite by activating the type 1 cholecystokinin receptor (CCK1R). Several drug development campaigns have focused on finding CCK1R-specific agonists, which showed promising efficacy for reducing meal size and weight, but fell short on FDA approval, likely due to side effects associated with potent, long-lasting activation of CCK1Rs. Positive allosteric modulators (PAMs) without inherent agonist activity have been proposed to overcome the shortcomings of traditional, orthosteric agonists and restore CCK1R signaling in failing physiologic systems. However, drug discovery campaigns searching for such novel acting CCK1R agents remain limited. Here we report a high-throughput screening effort and the establishment of a testing funnel, which led to the identification of novel CCK1R modulators. We utilized IP-One accumulation to develop robust functional equilibrium assays tailored to either detect PAMs, agonists or non-specific activators. In addition, we established the CCK1R multiplex PAM assay as a novel method to evaluate functional selectivity capable of recording CCK1R-induced cAMP accumulation and ß-arrestin recruitment in the same well. This selection and arrangement of methods enabled the discovery of three scaffolds, which we characterized and validated in an array of functional and binding assays. We found two hits incorporating a tetracyclic scaffold that significantly enhanced CCK signaling at CCK1Rs without intrinsically activating CCK1Rs in an overexpressing system. Our results demonstrate that a well-thought-out testing funnel can identify small molecules with a distinct pharmacological profile and provides an important milestone for the development of novel potential treatments of obesity.

Non-Opioid Peptides Targeting Opioid Effects.

Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.

Cholecystokinin-8 treatment reduces acinar necrosis and edema of pigs with induced pancreatitis.

BACKGROUND: Acute pancreatitis is an inflammatory process of the pancreas and a leading cause of hospitalization amongst gastrointestinal disorders. Previously, cholecystokinin (CCK) has been described to play a role in regeneration of pancreas. The aim of this study was to analyse the function of cholecystokinin octapeptide (CCK-8) during induced pancreatitis in an animal model. METHODS: Overall acute pancreatitis was induced in 38 pigs. After the induction of acute pancreatitis, half of the animals were treated with CCK-8. Intraoperative clinical data, postoperative blood parameters, 'Porcine Well-being' (PWB) and fitness score and post-mortal histopathological data were analysed. RESULTS: At baseline, physiologically parameters of the pigs of both groups were comparable. No differences were observed regarding the overall survival of animals (p = 0.97). Postoperative PWB score were significantly enhanced in animals treated with CCK-8 as compared to the control group (p = 0.029). Moreover, histopathological analysis of the pancreatic tissue revealed that acinar necrosis and edema were significant reduced in the CCK-8 group in comparison to the control group (p = 0.016 and p = 0.019). CONCLUSIONS: In conclusion, we found that CCK-8 treatment reduces acinar necrosis and edema of pancreatic tissue after induction of an acute pancreatitis in pigs.

Cholecystokinin Modulates the Mucosal Inflammatory Response and Prevents the Lipopolysaccharide-Induced Intestinal Epithelial Barrier Dysfunction.

The intestinal mucosa plays a critical role in the organism, acting as an interface between the lamina propria and the harmful antigens in the lumen. Sepsis is associated with primary injury to the intestinal mucosa, which in turn induces bacterial translocation and hyperpermeability. Cholecystokinin (CCK) is a peptide synthesized by several cell types, whose immunomodulatory activity has been reported in experimental models of inflammation. We hypothesized that the CCK treatment could modulate the inflammatory response and protect the integrity of the intestinal barrier in endotoxemic rats. Ten minutes before the endotoxemia induction by lipopolysaccharide (LPS) administration, rats were pretreated with CCK at two doses (0.4 µg/kg or 40 µg/kg). Mucosal permeability, bacterial translocation, cytokines production, histology injury, and expression of tight junction (TJ) proteins were the parameters assessed. In the early phase of endotoxemia, rats exhibited impaired intestinal barrier function, increased mucosal permeability, bacterial translocation, and also hyperactivation of the inflammatory response. On the other hand, the pretreatment with CCK modulated the mucosal production of pro-inflammatory cytokines and increased the expression of seal-forming TJ proteins (occludin, claudin-1 and junctional adhesion molecule (JAM-A)) only in the colon and also, reduced the bacterial counts in the mesenteric lymph nodes. However, CCK has a site-specific mechanism of action in the colon via CCK-1R, which is upregulated by the CCK treatment. In synergy with previous findings from our research group, the present results demonstrated that CCK preserves the integrity of the intestinal mucosa and might be a promising hormonal adjuvant therapy for the treatment of sepsis.

Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes.

Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival. Consequently, this has led to the development of enzymatically stable, biologically active, CCK peptide analogues with proposed therapeutic promise for both obesity and type 2 diabetes. In addition, several studies have demonstrated metabolic, and therapeutically relevant, complementary biological actions of CCK with those of the incretin hormones GIP and GLP-1, as well as with amylin and leptin. Thus, stable CCK derivatives not only offer promise as potential independent weight-reducing and glucose-lowering drugs, but also as effective adjunctive therapies. This review focuses on the recent and ongoing developments of CCK in the context of new therapies for obesity and type 2 diabetes.

Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.

AIM: To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents. METHODS: A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep(ob) /Lep(ob) mice for 28 days, and metabolic variables were assessed. RESULTS: Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lep(ob) /Lep(ob) mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups. CONCLUSIONS: The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

In vivo degradation of cholesterol to bile acids is reduced in patients receiving parenteral nutrition.

BACKGROUND: Artificial nutrition is frequently associated with hepatobiliary complications, probably due to the inherent derangement of the gastrointestinal tract physiology. Alterations of hepatic lipid metabolism are likely to be involved. The aim of the present study was to investigate the effect of artificial nutrition on bile acid production, a key event in cholesterol homeostasis, in humans. PATIENTS AND METHODS: Eleven patients receiving artificial nutrition, either parenteral nutrition (PN; n = 6) or enteral nutrition (EN; n = 5) with no previous history of liver disease, underwent analysis of cholesterol 7α-hydroxylation rates in vivo, a measure of bile acid formation, by isotope release analysis after intravenous injection of [7α-(3)H]cholesterol. The results were compared with those obtained in a population of 16 age-matched control subjects. RESULTS: Hydroxylation rates were lower in patients with artificial nutrition (PN: 94 ± 13 mg/d; EN: 230 ± 39 mg/d, mean ± SEM) when compared with controls (385 ± 47 mg/d) (P < .01, 1-way analysis of variance). In a patient receiving EN, hydroxylation rates increased 3.5-fold after treatment with the cholecystokinin analogue ceruletide (20 µg bid for 2 weeks intramuscularly). Serum lathosterol-to-cholesterol ratio, a marker of cholesterol synthesis, was also significantly reduced in artificial nutrition, whereas serum levels of fibroblast growth factor 19 (FGF19) were increased. CONCLUSION: In vivo 7α-hydroxylation is suppressed in artificial nutrition, particularly in PN. The finding associates with reduced cholesterol production, possibly as a metabolic consequence. The data suggest a regulatory role of gastrointestinal hormones and FGF19 on bile acid production and might suggest a pathophysiological basis for some common complications of artificial nutrition, such as gallstone disease and cholestasis.

Effects of cholecystokinin-8 on morphine-induced spatial reference memory impairment in mice.

Acute and chronic exposure to opiate drugs impaired various types of memory processes. To date, there is no preventive treatment for opiate-induced memory impairment and the related mechanism is still unclear. CCK-8 is the most potent endogenous anti-opioid peptide and has been shown to exert memory-enhancing effect, but the effect of CCK-8 on morphine-induced memory impairment has not been reported. By using Morris water maze, we found that escape latency to the hidden platform in navigation test was not influenced, but performance in the probe test was seriously poor in morphine dependency mice. Amnesia induced by chronic morphine treatment was significantly alleviated by pre-treatment with CCK-8 (0.01, 0.1 and 1 µg, i.c.v.), and CCK-8 (0.1 and 1 µg, i.c.v.) treatment alone could improve performance in either navigation or probe test. Furthermore, Golgi-Cox staining analysis revealed that pre-treatment with CCK-8 (1 µg, i.c.v.) reversed spine density decreased in CA1 region of hippocampus in morphine dependency mice, and CCK-8 (1 µg, i.c.v.) alone obviously increased spine density in CA1. Our findings conclude spine density change in CA1 region of hippocampus may be the structural plasticity mechanism which is responsible for enhancing effect of CCK-8 on spatial reference memory. Therefore, CCK-8 could effectively improve memory impairment in morphine dependency mice.

Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.

Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 µg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

[Experimental study of antidepressant effects of GB-115 dipeptide].

It was previously reported that GB-115 [Ph(CH2)5CO-Gly-D-Trp-NH2], a tryptophan-containing dipeptide analog of endogenous CCK4, exhibited pronounced anxiolytic effects in behavioral models of anxiety targeted on the "passive" phenotype of the emotional stress reaction. The aim of the present work was to study the modulator action of GB-115 (0.0125-0.1 mg/kg, i.p.) on emotional processes in both mongrel and inbred (BALB/c and C57B1/6) mice with opposite emotionality in Porsolt's test. GB-115 injected at a dose of 0.025 mg/kg led to a decrease in the immobilization time in all animals tested. The effect observed was less potent than that of amitriptyline (10 mg/kg). In contrast to the case of BALB/c mice, GB-115 increased the latent period in both C57B1/6 mice with active type of behavior and in mongrel mice. There were no changes in spontaneous locomotor activity after the acute administration of GB-115 in inbred and mongrel mice. It was found that GB-115 at an anxiolytic dose produced antidepressant-like effects independently of the genetically controlled emotional stress reaction phenotype. These results indicate that the novel dipeptide analog of CCK4 may have potential in the clinical management of concurrent anxiety and depression.

Bench-to-bedside review: the gut as an endocrine organ in the critically ill.

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.

Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem.

Behavioral effects of neuropeptides in rodent models of depression and anxiety.

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.

Obesity treatment: novel peripheral targets.

Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short- and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

Gut hormones: implications for the treatment of obesity.

Bariatric surgery is the only effective treatment for patients with morbid obesity. This is no solution to the present obesity pandemic however. Currently licensed non-surgical pharmaceuticals are of limited efficacy and alternatives are needed. Harnessing the body's own appetite-regulating signals is a desirable pharmacological strategy. The gastrointestinal tract has a prime role in sensing and signalling food intake to the brain. Gut hormones are key mediators of this information, including: peptide YY (PYY), pancreatic polypeptide (PP), glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), ghrelin, amylin and cholecystokinin (CCK). This review summarises the latest knowledge regarding the physiological and pathophysiological role of gut hormones in regulating our food intake and how this knowledge could guide, or has guided, the development of weight-loss drugs. Up-to-date outcomes of clinical trials are evaluated and directions for the future suggested.

The treatment of gallbladder dyskinesia based upon symptoms: results of a 2-year, prospective, nonrandomized, concurrent cohort study.

BACKGROUND: Gallbladder dyskinesia (GD) is controversial. We sought to determine the success rate of cholecystectomy or observation in treating patients with GD with intervention decisions based upon clearly defined symptoms. METHODS: Ninety-three consecutive patients with documented GD were enrolled into a 2-year prospective study. Based upon the presenting symptoms categorized as either classic for gallbladder pathology or atypical, patients underwent cholecystectomy (classic) or observation (atypical). We defined dyskinesia as a cholecystokinin (CCK)-stimulated ejection fraction (EF) <35% on nuclear cholescintigraphy and a negative gallbladder ultrasound. RESULTS: Classic gallbladder symptoms were identified in 61 patients and an atypical presentation occurred in 32 patients. The EF with CCK stimulation was not significantly different between the groups (19+/-9% vs. 16+/-7%, P=0.12). Of those with atypical symptoms, 28% (9 out of 32) had resolution of their symptoms without surgery. About 72% (23 out of 32) had worsening or progressive symptoms that did not resolve during observation, and later underwent surgery. Of these, 57% (13 out of 23) had resolution of their symptoms after surgery, but 43% (10 out of 23) had no improvement. Of those with classic symptoms, 60 patients underwent laparoscopic cholecystectomy with resolution of symptoms in 58 (97%). Patients with classic symptoms were 22 times more likely to have relief after cholecystectomy (odds ratio 22.3, P=0.0002). Eight patients had their symptoms recur more than 1 year after surgery (3 atypical and 5 classic) such that at long-term follow-up, cholecystectomy had helped only 43% of the atypical patients and 88% of the classic patients. CONCLUSIONS: Classic biliary symptoms are more predictive of success after cholecystectomy in patients with GD than is EF. The symptoms that are most predictive of success after surgery are right upper quadrant pain, pain after meals, and reproduction of the pain after CCK administration. Patients with atypical symptoms are much less likely to have improvement after surgery and should be observed; however, recurrent or progressive symptoms should prompt intervention if all additional testing is negative.

Emerging concepts in the medical and surgical treatment of obesity.

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.