cholecystokinin and Weight-Loss

Developing novel foods to suppress energy intake and promote negative energy balance and weight loss has been a long-term but commonly unsuccessful challenge. Targeting regulation of appetite is of interest to public health researchers and industry in the quest to develop 'functional' foods, but poor understanding of the underpinning mechanisms regulating food intake has hampered progress. The gastrointestinal (GI) or 'satiety' peptides including cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) secreted following a meal, have long been purported as predictive biomarkers of appetite response, including food intake. Whilst peptide infusion drives a clear change in hunger/fullness and eating behaviour, inducing GI-peptide secretion through diet may not, possibly due to modest effects of single meals on peptide levels. We conducted a review of 70 dietary preload (DIET) and peptide infusion (INFUSION) studies in lean healthy adults that reported outcomes of CCK, GLP-1 and PYY. DIET studies were acute preload interventions. INFUSION studies showed that minimum increase required to suppress ad libitum energy intake for CCK, GLP-1 and PYY was 3.6-, 4.0- and 3.1-fold, respectively, achieved through DIET in only 29%, 0% and 8% of interventions. Whether circulating 'thresholds' of peptide concentration likely required for behavioural change can be achieved through diet is questionable. As yet, no individual or group of peptides can be measured in blood to reliably predict feelings of hunger and food intake. Developing foods that successfully target enhanced secretion of GI-origin 'satiety' peptides for weight loss remains a significant challenge.

Topics: Anti-Obesity Agents; Appetite Regulation; Cholecystokinin; Eating; Energy Metabolism; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Infusions, Parenteral; Male; Peptide Hormones; Peptide YY; Satiety Response; Signal Transduction; Weight Loss

Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the gut incretin hormone glucagon-like peptide-1 (GLP-1). The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is an endoscopic deployable minimally invasive and fully reversible technique designed to mimic the bypass component of the RYGB. Not only GLP-1 is released when nutrients enter the gastrointestinal tract. Cholecystokinin (CCK), secreted from duodenal I cells, elicits gallbladder emptying. Traditionally, bile acids are thought of as essential elements for fat absorption. However, growing evidence suggests that bile acids have additional effects in metabolism. Thus, bile acids appear to increase GLP-1 secretion via activation of the TGR5 receptor on the intestinal L cell. Recently FXR receptors were postulated to contribute to GLP-1 secretion too. Furthermore, metformin has been shown to increase circulating GLP-1 levels but although the exact mechanism is not fully elucidated it may involve metformin-induced inhibition of bile acid reuptake from the small intestines. Small-sized studies reported varying degrees of weight loss and, in some, improvement of glucose metabolism. Therefore, the objectives of this thesis were to collect existing information on the DJBS in order to evaluate clinical efficacy and safety (study I and II). Furthermore, since the endocrine impact of the DJBS is not fully elucidated, and DJBS is expected to mimic RYGB, we investigated postprandial metabolic changes following 26 weeks of DJBS treatment in ten obese subjects with normal glucose tolerance (NGT) and nine matched patients with T2D (study III). Finally, we studied the single and combined effects of CCK induced gallbladder emptying and single-dose metformin on human GLP-1 secretion in ten healthy subjects (study IV). We hypothesized that metformin-induced GLP-1 secretion - at least partly - would be dependent on gallbladder emptying and the presence of bile acids in the gut. DJBS appears to lead to moderate weight losses in obese subjects compared to diet or lifestyle modifications (study II). DJBS had insignificant and small effects (compared to diet) on glycaemic regulation. Adverse events consisted mainly of mild-to-moderate tr

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cholecystokinin; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Incretins; Metformin; Obesity; Weight Loss

Childhood obesity is a global epidemic and associated with an increased risk of hypertension, diabetes mellitus, and coronary heart disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modifications are often unsuccessful because of disturbed perceptions of satiety. New signaling peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and pancreas communicate with brain centers of energy homeostasis, such as the hypothalamus and hindbrain. This review discusses the major known gut- and adipose tissue-derived hormones involved in the regulation of food intake and energy homeostasis and their serum levels in childhood obesity before and after weight loss as well as their relationship to consequences of obesity. Since most of the changes of gastrointestinal hormones and adipokines normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weight- and food intake-regulating gut- and adipose tissue-derived hormones will help to find new strategies to treat obesity and its consequences.

Topics: Adipokines; Adipose Tissue; Child; Cholecystokinin; Diabetes Mellitus, Type 2; Dipeptides; Enteropeptidase; Exercise; Glucagon-Like Peptide 1; Health Behavior; Health Promotion; Humans; Hypothalamus; Life Style; Obesity; Oxyntomodulin; Pancreatic Polypeptide; Rhombencephalon; Weight Loss

Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy.. During the review period, considerable progress occurred in the understanding of previously described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of the neuroendocrine regulation of energy homeostasis has been expanded.. Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical-weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging.

Topics: Adipose Tissue; Animals; Appetite Regulation; Cholecystokinin; Energy Intake; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Mice; Neurosecretory Systems; Obesity; Weight Loss

Bariatric surgery is the only effective treatment for morbid obesity in the long term. Gut hormones are key players in the metabolic mechanisms causing obesity. Furthermore gut hormones are involved in the signalling process of hunger and satiety which leads to the control of nutrient intake. In this review, the role of these hormones as facilitators of appetite control after bariatric and metabolic surgery will be explored.

Topics: Animals; Appetite Regulation; Bariatric Surgery; Cholecystokinin; Eating; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Obesity, Morbid; Peptide YY; Satiation; Satiety Response; Weight Loss

Measurement of gallbladder motility is a powerful research tool, but its value in clinical practice is uncertain. Three main conditions have been investigated for potential clinical application of this measurement. The first potential application is for identification of patients at risk of recurrence following gallstone dissolution with medical therapy. Results in this clinical setting are disappointing due to the low positive predictive value for gallstone recurrence in sluggish gallbladder emptying. The second potential application is for identification of obese patients at risk of gallstone formation during rapid weight loss. In this condition, a high negative predictive value has been reported for a normal gallbladder emptying pattern. The third potential application is for patients with recurrent biliary colic and acalcolous gallbladder disease. The diagnostic value of a provocative test involving intravenous cholecystokinin injection as a method of identifying patients likely to benefit from cholecystectomy is uncertain, partly as a consequence of non-standardized methodology. The balance of evidence reported in this review suggests a low inherent value of measurement of gallbladder motility in clinical practice. Acalcolous gallbladder disease is the clinical setting deserving further investigation on the value of the cholecystokinin provocative test, but this test needs to be standardized.

Topics: Acalculous Cholecystitis; Cholecystography; Cholecystokinin; Gallbladder; Gallbladder Emptying; Gallstones; Humans; Postprandial Period; Ultrasonography; Weight Loss

Diet-induced weight loss (WL) is usually accompanied by increased appetite, a response that seems to be absent when ketogenic diets are used. It remains unknown if sex modulates the appetite suppressant effect of ketosis.. The aim of this study was to examine if sex modulates the impact of WL-induced changes in appetite and if ketosis alters these responses.. Ninety-five individuals (55 females) with obesity (BMI [kg/m 2]: 37  ± 4) underwent 8 wk of a very-low-energy diet, followed by 4 wk of refeeding and weight stabilization. Body composition, plasma concentration of β-hydroxybutyrate (β-HB) and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY [PYY], cholecystokinin and insulin), and subjective feelings of appetite were measured at baseline, week 9 in ketosis, and week 13 out of ketosis.. The mean WL at week 9 was 17% for males and 15% for females, which was maintained at week 13. Weight, fat, and fat-free mass loss were greater in males (P < 0.001 for all) and the increase in β-HB at week 9 higher in females (1.174 ± 0.096 compared with 0.783 ± 0.112 mmol/L, P = 0.029). Basal and postprandial GLP-1 and postprandial PYY (all P < 0.05) were significantly different for males and females. There were no significant sex × time interactions for any other appetite-related hormones or subjective feelings of appetite. At week 9, basal GLP-1 was decreased only in males (P < 0.001), whereas postprandial GLP-1 was increased only in females (P < 0.001). No significant changes in postprandial PYY were observed over time for either sex.. Ketosis appears to have a greater beneficial impact on GLP-1 in females. However, sex does not seem to modulate the changes in the secretion of other appetite-related hormones, or subjective feelings of appetite, seen with WL, regardless of the ketotic state. This trial was registered at clinicaltrials.gov as NCT01834859.

Topics: Adolescent; Adult; Aged; Appetite; Cholecystokinin; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Ketosis; Male; Middle Aged; Obesity; Peptide YY; Sex Factors; Weight Loss; Young Adult

Strong compensatory responses, with reduced resting metabolic rate (RMR), increased exercise efficiency (ExEff) and appetite, are activated when weight loss (WL) is achieved with continuous energy restriction (CER), which try to restore energy balance. Intermittent energy restriction (IER), where short spells of energy restriction are interspaced by periods of habitual energy intake, may offer some protection in minimizing those responses. We aimed to compare the effect of IER versus CER on body composition and the compensatory responses induced by WL.. Changes in body weight (≈12.5% WL) and composition were similar in both groups. Fasting RQ and ExEff at 10 W increased in both groups. Losing weight, either by IER or CER dieting, did not induce significant changes in subjective appetite ratings. RMR decreased and ExEff at 25 and 50 W increased (P < 0.001 for all) in IER group only. Basal and postprandial AG increased (P < 0.05) in IER group, whereas basal active GLP-1 decreased (P = 0.033) in CER group only. Postprandial CCK decreased in both groups (P = 0.0012 and P = 0.009 for IER and CER groups, respectively). No between group differences were apparent for any of the outcomes.. The technique used to achieve energy restriction, whether it is continuous or intermittent, does not appear to modulate the compensatory mechanisms activated by weight loss.. NCT02169778 (the study was registered in clinicaltrial.gov).

Topics: Adult; Basal Metabolism; Body Composition; Body Weight; Caloric Restriction; Cholecystokinin; Diet, Reducing; Eating; Energy Intake; Exercise; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Middle Aged; Norway; Obesity; Oxygen Consumption; Peptide YY; Weight Loss

"Living High-Training Low" (LHTL) is effective for the improvement of athletic ability; however, little is known about the effect of LHTL on obese individuals. The present study determined whether LHTL would have favorable influence on body composition, rebalance the appetite hormones, and explore the underlying mechanism.. Adolescents with obesity [body mass index (BMI) >30 kg/m] were randomly assigned to "Living Low-Training Low" (LLTL, n = 19) group that slept in a normobaric normoxia condition and the LHTL (n = 16) group slept in a normobaric hypoxia room (14.7% PO2 ∼2700 m). Both groups underwent the same aerobic exercise training program. Morphological, blood lipids, and appetite hormones were measured and assessed.. After the intervention, the body composition improved in both groups, whereas reductions in body weight (BW), BMI, and lean body mass increased significantly in the LHTL group (all, P < .05). In the LLTL group, cholecystokinin (CCK) decreased remarkably (P < .05) and CCK changes were positively associated with changes in BW (r = 0.585, P = .011) and BMI (r = 0.587, P = .010). However, in the LHTL group, changes in plasma glucagon-like peptide-1 (GLP-1) and interleukin-6 (IL-6) levels, positively correlated with each other (r = 0.708, P = .015) but negatively with BW changes (r = -0.608, P = .027 and r = -0.518, P = .048, respectively).. The results indicated that LHTL could induce more weight loss safely and efficiently as compared to LLTL and increase the plasma GLP-1 levels that may be mediated by IL-6 to rebalance the appetite. Thus, an efficient method to treat obesity and prevent weight regain by appetite rebalance in hypoxia condition was established.

Topics: Adolescent; Body Composition; Body Mass Index; Cholecystokinin; Exercise; Female; Glucagon-Like Peptide 1; Humans; Hyperbaric Oxygenation; Hypoxia; Interleukin-6; Male; Pediatric Obesity; Pilot Projects; Treatment Outcome; Weight Loss; Weight Reduction Programs

Satiety is centrally and peripherally mediated by gastrointestinal peptides and the vagal nerve. We aimed to investigate whether intragastric balloon treatment affects satiety through effects on fasting and meal-stimulated cholecystokinin (CCK) and pancreatic polypeptide (PP) secretion.. Patients referred for obesity treatment were randomised to 13 weeks of sham treatment followed by 13 weeks of balloon treatment (group 1; sham/balloon) or to twice a 13-week period of balloon treatment (group 2; balloon/balloon). Blood samples were taken for fasting and meal-stimulated CCK and PP levels at the start (T0) and after 13 (T1) and 26 (T2) weeks. Patients filled out visual analogue scales (VAS) to assess satiety.. Forty-two patients (35 females, body weight 125.1 kg, BMI 43.3 kg/m(2)) participated. In group 1, basal CCK levels decreased but meal-stimulated response remained unchanged after 13 weeks of sham treatment. In group 2, basal and meal-stimulated CCK levels decreased after 13 weeks of balloon treatment. At the end of the second 13-week period, when group 1 had their first balloon treatment, they duplicated the initial 13-week results of group 2, whereas group 2 continued their balloon treatment and reduced meal-stimulated CCK release. Both groups showed reduced meal-stimulated PP secretions at T1 and T2 compared to T0. Changes in diet composition and VAS scores were similar. Improvements in glucose homeostasis partly explained the PP results.. The reduced CCK and PP secretion after balloon positioning was unexpected and may reflect delayed gastric emptying induced by the balloon. Improved glucose metabolism partly explained the reduced PP secretion. Satiety and weight loss were not adversely influenced by these hormonal changes.

Topics: Adult; Cholecystokinin; Eating; Fasting; Female; Gastric Balloon; Humans; Male; Middle Aged; Obesity; Pain Measurement; Pancreatic Polypeptide; Postprandial Period; Satiation; Treatment Outcome; Weight Loss

The mechanisms of amelioration of glycemic control early after laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) are not fully understood.. In this prospective, randomized 1-year trial, outcomes of LRYGB and LSG patients were compared, focusing on possibly responsible mechanisms. Twelve patients were randomized to LRYGB and 11 to LSG. These non-diabetic patients were investigated before and 1 week, 3 months, and 12 months after surgery. A standard test meal was given after an overnight fast, and blood samples were collected before, during, and after food intake for hormone profiles (cholecystokinin (CCK), ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY)).. In both groups, body weight and BMI decreased markedly and comparably leading to an identical improvement of abnormal glycemic control (HOMA index). Post-surgery, patients had markedly increased postprandial plasma GLP-1 and PYY levels (p < 0.05) with ensuing improvement in glucose homeostasis. At 12 months, LRYGB ghrelin levels approached preoperative values. The postprandial, physiologic fluctuation returned, however, while LSG ghrelin levels were still markedly attenuated. One year postoperatively, CCK concentrations after test meals increased less in the LRYGB group than they did in the LSG group, with the latter showing significantly higher maximal CCK concentrations (p < 0.012 vs. LRYGB).. Bypassing the foregut is not the only mechanism responsible for improved glucose homeostasis. The balance between foregut (ghrelin, CCK) and hindgut (GLP-1, PYY) hormones is a key to understanding the underlying mechanisms.

Topics: Adult; Blood Glucose; Cholecystokinin; Female; Gastric Bypass; Gastrointestinal Hormones; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Laparoscopy; Male; Obesity, Morbid; Peptide YY; Postprandial Period; Prospective Studies; Weight Loss

Obesity is an energy balance problem caused by overeating. Obesity treatment includes diet, exercise, behaviour treatment, pharmacotherapy and surgery; in addition, acupuncture is also an option.. To investigate the effect of acupuncture on weight loss and whether a brief acupuncture treatment of 5 weeks can change circulating levels of leptin, ghrelin, insulin and cholecystokinin (CCK) in obese women.. 40 women with a body mass index (BMI)>30 kg/m(2) were equally randomised to either an acupuncture group or a sham (non-penetrating) acupuncture group and received treatment at LI4, HT7, ST36, ST44 and SP6 bilaterally. Both groups had two sessions of 20 min/week for a total of 10 sessions. Serum insulin, leptin, plasma ghrelin and CCK levels were measured by ELISA.. Acupuncture treatment decreased insulin and leptin levels and induced weight loss, together with a decrease in BMI compared with sham acupuncture. Furthermore, between-group analyses demonstrated increases in plasma ghrelin and CCK levels in subjects who received acupuncture treatment.. These findings suggest that acupuncture may help to regulate weight owing to its beneficial effects on hormones such as insulin, leptin, ghrelin and CCK in obese subjects even after a few weeks of treatment.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Body Mass Index; Cholecystokinin; Female; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Obesity; Weight Loss

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.. We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.. Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).. One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.).

Topics: Body Mass Index; Body Weight; Cholecystokinin; Diet, Reducing; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Intention to Treat Analysis; Leptin; Male; Middle Aged; Obesity; Peptide YY; Peptides; Postmenopause; Weight Loss

To assess weight maintenance after weight loss by consumption of yoghurt with a novel fat emulsion (Olibra) including effects on body composition, resting energy expenditure (REE), fat oxidation, hunger feelings and satiety hormones.. A randomized, placebo-controlled, double-blind, parallel design. A 6-week weight loss period (2.1 MJ/day) was followed by 18 weeks weight maintenance with test (Olibra) or placebo yoghurt.. Fifty overweight women (age: 18-58 years, body mass index (BMI) 25-32 kg/m2).. In weeks 1, 7 and 25, a satiety test with questionnaires and blood samples for analysis of satiety hormones. In weeks 2, 8 and 26, REE, body weight and body composition.. During weight maintenance after significant body weight reduction, there was no significant increase in body weight in the test group (1.1+/-3.4 kg); the placebo group did gain weight (3.0+/-3.1 kg, P<0.001). Compared to the placebo group, the test group was less hungry 4 h after yoghurt consumption in week 25 (P<0.05) and showed increased glucagon like peptide-1 values 180 min after yoghurt consumption (week 25 vs week 1, P<0.05). Measured REE as a function of fat-free mass (FFM) was significantly higher than predicted REE (P<0.05) in week 26 for the test group, but not for the placebo group. Fat mass (FM) was significantly more decreased in the test group (6.5+/-4.1 kg) compared to the placebo group (4.1+/-3.6 kg) (week 26 vs week 2, P<0.05).. Consumption of Olibra yoghurt improved weight maintenance compared to placebo, which can be explained by the relatively higher REE as a function of FFM, relatively higher decrease in FM and the relatively lower increase in hunger.

Topics: Adolescent; Adult; Appetite Depressants; Body Mass Index; Body Weight; Caloric Restriction; Cholecystokinin; Dietary Supplements; Double-Blind Method; Emulsions; Energy Metabolism; Fats; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Middle Aged; Obesity; Overweight; Peptide Hormones; Satiety Response; Weight Gain; Weight Loss; Yogurt

Accelerated gastric emptying of solids may play a role in the pathogenesis of obesity. Orlistat, a potent lipase inhibitor, induces fat malabsorption and body weight loss but might accelerate gastric emptying as a result of suppressed CCK release. The aim was to investigate the role of fat restriction and lipase inhibition in CCK release and gastric emptying.. A total of 28 patients (three male (M)/25 female (F); mean (s.d.) BMI 37.4(3.9) kg/m2) entering a randomized, double-blind, placebo-controlled study.. CCK release and gastric emptying by scintigraphy at the start (T0), after 1 month of an energy- and fat-restricted diet and placebo (T1), and after 1 month (T2) and 1 year (T3) of randomization to placebo or 120 mg orlistat three times a day.. One month of dieting and a weight loss of 2.3 kg (2.1% of initial weight) did not affect gastric emptying of liquids and solids. Basal and meal-stimulated CCK levels remained unaltered. Placebo-treated subjects who continued the diet for 1 month demonstrated a borderline significant suppressed CCK secretion and a weight loss of 1.2 kg (1.0%) without an effect on gastric emptying. After 1 year, the CCK secretion recovered to or beyond values at the start. A significantly slower emptying of solids (17.6 (T3) versus 25.9 (T1)%/h) and a weight loss of 10.4 kg (9.9%) was observed. Subjects on 120 mg orlistat lost 2.5 kg (2.5%) after 1 month, and 9.8 kg (9.9%) after 1 year. Basal and postprandial CCK release decreased significantly after the first month of orlistat treatment but normalized after 1 year. Diet and lipase inhibition did not have any influence on gastric emptying.. Energy and fat restriction of 1 month did not alter gastric emptying in the whole group. Continuation of the diet for 1 year resulted in a delayed gastric emptying of solids. Lipase inhibition did not result in a sustained depressed CCK release and the anticipated acceleration of gastric emptying did not occur.

Topics: Anti-Obesity Agents; Cholecystokinin; Diet, Fat-Restricted; Diet, Reducing; Enzyme Inhibitors; Female; Gastric Emptying; Humans; Lactones; Lipase; Male; Middle Aged; Obesity; Orlistat; Satiety Response; Weight Loss

Obese subjects are at risk of developing gallstones as a result of the obese state and during weight reduction.. To study whether orlistat, by lipase inhibition, impairs gall-bladder emptying, thus further predisposing weight-losing obese subjects to gallstone formation.. Patients entering a randomized clinical trial of 1 month of diet, followed by treatment with placebo, 3 x 60 mg orlistat or 3 x 120 mg orlistat, underwent gall-bladder emptying studies measured by ultrasound. Meal-induced cholecystokinin release and gall-bladder emptying were investigated at the start, at randomization and after 1 and 12 months.. One month of dieting did not change gall-bladder emptying and cholecystokinin release. After 1 month, placebo treatment resulted in a decreased fasting volume of 11%, compared with increases of 26% and 47% with 60 and 120 mg orlistat, respectively. Gall-bladder emptying increased by 9% with placebo and decreased by 15% and 53% with 60 and 120 mg orlistat, respectively. Fasting cholecystokinin values and cholecystokinin release decreased significantly in the orlistat group. After 1 year, a persistent but attenuated effect of orlistat on gall-bladder emptying and cholecystokinin release remained. Three of 40 patients developed gallstones, two on placebo with major weight loss and one on 60 mg orlistat.. One month of lipase inhibition by orlistat significantly impaired gall-bladder motility, which persisted to some extent after 1 year. Obese subjects with diabetes or hyperlipidaemia, who are more at risk of gallstones, should be followed carefully.

Topics: Adult; Anti-Obesity Agents; Body Weight; Cholecystokinin; Female; Gallbladder; Humans; Lactones; Lipase; Male; Middle Aged; Obesity; Orlistat; Weight Loss

To investigate the weight-reducing effect of cimetidine in overweight patients with Type 2 diabetes.. A 12-week clinical intervention study of 400 mg cimetidine prescribed three times daily in a randomised, double-blind, placebo-controlled design.. Forty-three overweight patients with Type 2 diabetes (age 18-65 y, body mass index (BMI) 27.2-48.2 kg/m2).. Body weight, BMI, body fat, waist and hip circumference, waist/hip ratio, blood pressure, fasting blood glucose, HbA1c, plasma concentrations of insulin, insulin/glucose ratio and lipids at the start and after 12 weeks, and daily recordings of appetite.. Subjects given cimetidine (n = 19) and placebo (n = 24) lost 5.0 +/- 2.2 kg (mean +/- s.d.) and 1.3 +/- 1.1 kg, respectively. Significant reductions were observed in appetite, body fat (29.9 +/- 6.6% to 25.3 +/- 7.4%), waist circumference (111.5 +/- 10.3 cm to 107.4 +/- 10.6 cm), waist/hip ratio (0.96 +/- 0.08 to 0.94 +/- 0.08), and systolic and diastolic blood pressure (reductions of 6.9 +/- 11.4 mm Hg and 6.0 +/- 6.6 mm Hg, respectively) in cimetidine group only. Significant decreases in fasting concentrations of blood glucose, HbA1c, plasma insulin, insulin/glucose ratio, plasma triglycerides and a significant increase in plasma high-density lipoprotein cholesterol were observed in the cimetidine group only.. Cimetidine reduces appetite and body weight, and improves metabolic control in overweight subjects with Type 2 diabetes.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Constitution; Cholecystokinin; Cholesterol, HDL; Cimetidine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Histamine H2 Antagonists; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Triglycerides; Weight Loss

After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure.. Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting.. On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]).. Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

Topics: Cholecystokinin; Eating; Female; Gastric Bypass; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Octreotide; Peptide YY; Weight Loss

To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate.. Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.. Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.. GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Topics: Agouti-Related Protein; Animals; Anorexia; Body Weight; Cholecystokinin; Eating; Glucagon-Like Peptides; Growth Differentiation Factor 15; Mice; Rats; Weight Loss

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. It was documented previously that co-administration of a cholecystokinin receptor-1 receptor (CCK-1R) agonist with a glucagon-like peptide-1 receptor (GLP-1R) agonist exerted improved effects on metabolic improvements in obese rodents. Here, we reported a series of novel GLP-1R/CCK-1R co-agonists constructed by linking the C-terminus of a GLP-1R agonist (native GLP-1 or Xenopus GLP-1) to the N-terminus of a CCK-1R selective agonist NN9056. The stability of co-agonists was further enhanced by introducing an albumin binding motif. In vitro functional assays revealed that the co-agonists retained full agonism potency on GLP-1R and CCK-1R. Particularly, 2a and 2c showed higher hypoglycemic and insulinotropic activities than NN9056 and semaglutide. The glucose-lowering durations and PK profiles of 2a and 2c were comparable to those of semaglutide. Desirably, in diet induced obesity (DIO) mice, 2a and 2c exhibited superior metabolic benefits to NN9056 and semaglutide in reducing food intake, inducing body weight loss, and regulating lipid metabolism. In short- and long-term studies in diabetic db/db mice, 2a and 2c showed enhanced effects on HbA1c, glucose tolerance, and pancreas function restoration compared with semaglutide. Importantly, no side effects, toxicities, or pancreatic inflammation were caused by 2a and 2c treatments. These preclinical studies suggest that the pharmacological effects of CCK-1 and GLP-1 pathways can be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

Topics: Animals; Cholecystokinin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Mice; Peptides; Receptors, Cholecystokinin; Weight Loss

Excluding the foregut (distal stomach and duodenum) from food transit in RYGB normalizes glucose tolerance. Excluding/removing the duodenal mucosa partly improves glycemic control. So far, the effect of excluding/removing the gastric mucosa remains unknown.. To observe the effect of removing the distal gastric mucosa on glucose tolerance.. Thirty fatty Sprague-Dawley rats received low-dose streptozotocin (STZ) to induce type 2 diabetes (T2D), then randomly assigned to Roux-en-Y gastric bypass (RYGB, n = 8), distal gastric mucosa removal (DGMR, n = 8), duodenal-jejunal bypass (DJB, n = 8), and Sham (n = 6) groups. In the DGMR group, the distal third of the gastric mucosa was removed by thermal ablation using an electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed-meal tolerance test (MMTT) were repeated 3 and 6 weeks postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded.. Gastrin AUC decreased significantly (p < 0.05) in the DGMR group after surgery. A significantly increased GLP-1 AUC was found in the RYGB, DGMR, and DJB groups at week 3 and only the RYGB group at week 6 postoperatively. The improved glucose tolerance in the RYGB group was significantly greater than the improved glucose tolerance in the DGMR and DJB groups. The improved glucose tolerance 3 and 6 weeks after surgery in the DGMR group was significantly greater than the improved glucose tolerance in the DJB group. Body weight decreased significantly in the RYGB, DGMR, and DJB groups postoperatively.. Removing the distal gastric mucosa induced significant weight loss and improved glycemic control in T2D SD rat model. Therefore, the gastric mucosa exclusion in RYGB may be key to the weight loss and diabetes remission, which perhaps warrants a new theory.

Topics: Animals; Area Under Curve; Bile Acids and Salts; Blood Glucose; Body Weight; C-Reactive Protein; Cholecystokinin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Feeding Behavior; Gastric Bypass; Gastric Mucosa; Glucose Tolerance Test; Glycemic Control; Insulin; Male; Rats, Sprague-Dawley; Weight Loss

To compare appetite markers in reduced-obese individuals with a nonobese control group.. A total of 34 adults with obesity who lost 17% body weight at week 13 and maintained this weight loss (WL) at 1 year were compared with 33 nonobese controls matched for body composition. Basal and postprandial subjective appetite ratings and appetite-related hormone concentrations (ghrelin, total peptide YY, peptide YY3-36, total and active glucagon-like peptide 1, and cholecystokinin) were measured in all participants and repeated at week 13 and 1 year in the weight-reduced group.. WL led to a reduction in prospective food consumption and an increase in feelings of hunger, fullness, and ghrelin secretion (basal and postprandial), but these new ratings were no different from those seen in controls. Postprandial concentrations of active glucagon-like peptide 1, total peptide YY, and cholecystokinin were lower in individuals with obesity at all time points compared with controls.. The increased drive to eat (both subjective feelings of hunger and ghrelin concentrations) seen in reduced-obese individuals, both after acute and sustained WL, reflects a normalization toward a lower body weight. Overall, WL does not have a sustained negative impact on satiety peptide secretion, despite a blunted secretion in individuals with obesity compared with nonobese controls.

Topics: Adult; Appetite; Body Mass Index; Body Weight; Cholecystokinin; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Male; Middle Aged; Obesity; Peptide YY; Satiation; Weight Loss

Sleeve gastrectomy with ileal transposition has been shown to be superior to sleeve gastrectomy alone for promoting weight loss in rat and porcine models. The absence of a mouse model for this procedure has impeded efforts to understand the molecular physiology underlying its efficacy. This study demonstrates the long-term survivability of sleeve gastrectomy with ileal transposition in mice.. In this study of technical feasibility, a sleeve gastrectomy with ileal transposition (SGIT), sleeve gastrectomy (SG), or sham surgery (SH) was performed on 7- to 8-week-old C57Bl/6J mice (n = 8 for each). To evaluate long-term survivability, mice were placed on an obesogenic diet and weighed weekly for 10 weeks. The intestinal identity of the transposed segment was assessed with gene expression analysis of duodenal-, jejunal-, and ileal-specific hormones using quantitative polymerase chain reaction.. Overall, SGIT better prevented weight gain than the SG or sham procedures (10-week post-operative weight: SH 45.3 ± 1.0 g, SG 41.25 ± 1.6 g, SGIT 35.4 ± 0.8 g). Gene expression pattern analysis of three markers of intestinal identity (gastrin, cholecystokinin, and peptide YY) suggests that the ileal identity of the transposed segment is maintained 10 weeks after transposition.. We demonstrate for the first time a reproducible mouse model of sleeve gastrectomy with ileal transposition. Future studies utilizing this model will expand our understanding of the molecular pathways through which the hindgut regulates satiety.

Topics: Animals; Biomarkers; Blood Glucose; Cholecystokinin; Disease Models, Animal; Feasibility Studies; Gastrectomy; Gastrins; Gene Expression; Ileum; Mice, Inbred C57BL; Peptide YY; Random Allocation; RNA; Weight Loss

Investigations into the relationship between dietary carbohydrate restriction and health are mixed. Current guidelines for nutrition promote low-fat foods and higher carbohydrate consumption for optimal health and weight loss. However, high-fat, low-carbohydrate diets are revealing both intra- and extracellular adaptations that have been shown to elicit favorable cardiometabolic changes associated with obesity. Moreover, dietary fat is associated with higher satiety levels from the hormones adiponectin, leptin, and cholecystokinin. Additionally, insulin responses from high-glycemic carbohydrates are known to alter these pathways, potentially leading to an increase in energy consumption and a possible mechanism for obesity.. There is convincing evidence of beneficial effects of controlled trials implementing high-fat, low-carbohydrate diets in both sedentary and obese individuals, but longer duration clinical trials are required to confirm this hypothesis.

Topics: Adiponectin; Cholecystokinin; Diet, Carbohydrate-Restricted; Diet, High-Fat; Energy Intake; Humans; Insulin; Leptin; Nutrition Policy; Obesity; Satiation; Weight Loss

Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety. In functional in vitro assays C2816 retained full agonism at GLP-1R and CCKR1 at lower potency compared to parent molecules, whereas a previously reported fusion peptide in the opposite orientation, (pGlu-Gln)-CCK-8/exendin-4, exhibited no activity at either receptor. Acutely, in vivo, C2816 increased cFos in key central nuclei relevant to feeding behavior, and reduced food intake in wildtype (WT), but less so in GLP-1R-deficient (GLP-1RKO), mice. In sub-chronic studies in diet-induced obese (DIO) mice, C2816 exerted superior reduction in body weight compared to co-administration of AC3174 and AC170222 albeit at a higher molar dose. These data suggest that the synergistic pharmacological effects of GLP-1 and CCK pathways can be harnessed in a single therapeutic peptide.

Topics: Animals; Anti-Obesity Agents; Brain; Cholecystokinin; Drug Synergism; Eating; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptides; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Weight Loss

Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low-energy diet (VLED).. Thirty-one sedentary adults (18 men), with obesity (body mass index: 37±4.5 kg m. A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both).. WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.

Topics: Adult; Appetite Regulation; Area Under Curve; Body Mass Index; Cholecystokinin; Diet, Ketogenic; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Longitudinal Studies; Male; Middle Aged; Norway; Obesity; Peptide YY; Postprandial Period; Satiety Response; Time Factors; Weight Loss

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.

Topics: Animals; Anti-Obesity Agents; Aorta; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Male; Obesity; Peptide Fragments; Rats, Sprague-Dawley; Satiation; Time Factors; Weight Loss

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.

Topics: Animals; Body Weight; Cholecystokinin; Diet; Drug Therapy, Combination; Gastrin-Releasing Peptide; Gastrointestinal Agents; Infusions, Parenteral; Male; Obesity; Peptide Fragments; Rats; Weight Loss

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.. 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.. 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.. The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Topics: Acetylation; Animals; Anti-Obesity Agents; Cholecystokinin; Diabetes Mellitus; Diet, High-Fat; Drug Synergism; Drug Therapy, Combination; Energy Intake; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Infusions, Subcutaneous; Islet Amyloid Polypeptide; Male; Mice, Mutant Strains; Obesity; Peptides; Random Allocation; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Glucagon; Weight Loss

Gastrointestinal hormones are critically involved in the regulation of food intake and body weight. Previous studies support an interplay between gastrointestinal hormones and the serotonergic system. This study explored intestinal neuroendocrine expression patterns in humans with obesity versus nonobese humans.. Jejunum samples were collected from 164 humans with obesity (120 women; BMI (mean ± SD): 43.5 ± 6.6 kg/m(2) ) while they underwent Roux-en-Y gastric bypass surgery and from 18 nonobese humans (7 women; BMI: 23.5 ± 3.0 kg/m(2) ) undergoing distinct intestinal surgeries. mRNA expression of cholecystokinin (CCK), peptide YY3-36 (PYY), nesfatin1, ghrelin, ghrelin O-acyltransferase (GOAT), leptin, leptin receptor (leptinR), glucagon-like-peptide 1 receptor (GLP1R), serotonin transporter (SERT), tryptophan hydroxylase 1 (TPH1), and serotonin receptor 3A (5HT3A R) was determined with qRT-PCR. Ghrelin and GOAT protein expression was quantified using immunohistological stainings. Statistical analyses were performed with SPSS.. Jejunum samples from humans with obesity showed a higher expression of GOAT (mRNA and protein), TPH1, and SERT mRNA compared with the nonobese humans (all P < 0.05). Positive correlations were observed between TPH1, CCK, PYY, and nesfatin1 in nonobese and GOAT, ghrelin, TPH1, SERT, CCK, and PYY in humans with obesity (all P < 0.01).. Our top-down approach substantiates the dysregulation of jejunal neuroendocrine hormones in obesity.

Topics: Acyltransferases; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cholecystokinin; Female; Gastric Bypass; Gastrointestinal Hormones; Gene Expression Regulation; Ghrelin; Humans; Jejunum; Leptin; Middle Aged; Neuroendocrine Cells; Obesity, Morbid; Peptide Fragments; Peptide YY; Weight Loss; Young Adult

To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB).. Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender.. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite.. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition.. Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

Topics: Absorptiometry, Photon; Appetite Regulation; Bile Acids and Salts; Blood Glucose; Body Mass Index; Cholecystokinin; Cross-Sectional Studies; Dumping Syndrome; Energy Metabolism; Female; Follow-Up Studies; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Neurotensin; Obesity, Morbid; Peptide YY; Treatment Outcome; Weight Loss

Hypoxia has been shown to reduce energy intake and lead to weight loss, but the underlying mechanisms are unclear. The aim was therefore to assess changes in eating after rapid ascent to 4,559 m and to investigate to what extent hypoxia, acute mountain sickness (AMS), food preferences and satiation hormones influence eating behavior.. Participants (n = 23) were studied at near sea level (Zurich (ZH), 446 m) and on two days after rapid ascent to Capanna Margherita (MG) at 4,559 m (MG2 and MG4). Changes in appetite, food preferences and energy intake in an ad libitum meal were assessed. Plasma concentrations of cholecystokinin, peptide tyrosine-tyrosine, gastrin, glucagon and amylin were measured. Peripheral oxygen saturation (SpO(2)) was monitored, and AMS assessed using the Lake Louis score.. Energy intake from the ad libitum meal was reduced on MG2 compared to ZH (643 ± 308 vs. 952 ± 458 kcal, p = 0.001), but was similar to ZH on MG4 (890 ± 298 kcal). Energy intake on all test days was correlated with hunger/satiety scores prior to the meal and AMS scores on MG2 but not with SpO(2) on any of the 3 days. Liking for high-fat foods before a meal predicted subsequent energy intake on all days. None of the satiation hormones showed significant differences between the 3 days.. Reduced energy intake after rapid ascent to high altitude is associated with AMS severity. This effect was not directly associated with hypoxia or changes in gastrointestinal hormones. Other peripheral and central factors appear to reduce food intake at high altitude.

Topics: Adult; Altitude; Altitude Sickness; Appetite; Body Mass Index; Cholecystokinin; Dexamethasone; Dipeptides; Eating; Energy Intake; Feeding Behavior; Female; Food Preferences; Gastrins; Glucagon; Humans; Hunger; Islet Amyloid Polypeptide; Male; Middle Aged; Satiation; Surveys and Questionnaires; Weight Loss; Young Adult

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping).. We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance.. Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests.. Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.

Topics: Adult; Appetite; C-Peptide; Cholecystokinin; Confounding Factors, Epidemiologic; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Somatostatin; Time Factors; Weight Loss

Losing weight can pose a challenge, but how to avoid putting those pounds back on can be a real struggle. A major health problem for obese people is that diseases linked to obesity, such as type 2 diabetes and cardiovascular disease, put their lives at risk, even in young individuals. Although bariatric surgery-a surgical method to reduce or modify the gastrointestinal tract-was originally envisioned for the most severe cases of obesity, evidence suggests that the benefit of this procedure may not be limited to the staggering weight loss it causes. Endogenous factors released from the gut, and modified after surgery, may explain why bariatric surgery can be beneficial for obesity-related diseases and why operated individuals successfully maintain the weight loss. In 'Bedside to Bench,' Rachel Larder and Stephen O'Rahilly peruse a human study with dieters who regained weight despite a successful diet. Appetite-regulating hormones in the gut may be responsible for this relapse in the long term. In 'Bench to Bedside,' Keval Chandarana and Rachel Batterham examine how two different methods of bariatric surgery highlight the relevance of gut-derived hormones not only in inducing sustained weight loss but also in improving glucose homeostasis. These insights may open new avenues to bypass the surgery and obtain the same results with targeted drugs.

Topics: Bariatric Surgery; Cholecystokinin; Glucagon-Like Peptide 1; Glucose; Humans; Obesity; Peptide YY; Weight Loss

Despite the fact that ∼85% of bariatric operations are performed in women, the effects of the reproductive axis function on outcome of bariatric surgery remain to be determined. Here we developed the first published model of Roux-en-Y gastric bypass (RYGB) in female rats. We show in ovariectomized rats receiving estradiol or control treatment that (1) RYGB-induced body weight loss and (2) the satiating efficacy of endogenous glucagon-like peptide-1 and cholecystokinin satiation were significantly increased in estradiol-treated rats. These data are relevant to the care of obese women, in particular perimenopausal women, undergoing bariatric surgery.

Topics: Animals; Biomarkers; Cholecystokinin; Estradiol; Estrogens; Feeding Behavior; Female; Gastric Bypass; Glucagon-Like Peptide 1; Menopause; Models, Animal; Obesity; Ovariectomy; Rats; Satiation; Treatment Outcome; Weight Loss

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.

Topics: Amyloid; Analysis of Variance; Animals; Appetite Depressants; Area Postrema; Body Weight; Cholecystokinin; Disease Models, Animal; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Islet Amyloid Polypeptide; Leptin; Male; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Weight Loss

Food intake, eating behavior, and metabolic parameters in rats that underwent bilateral truncal vagotomy, sleeve gastrectomy, and duodenal switch procedures were examined.. Rats were subjected to bilateral truncal vagotomy plus pyloroplasty (VTPP), pyloroplasty (PP), laparotomy, sleeve gastrectomy (SG), or duodenal switch (DS; with and without SG).. VTPP, but neither PP nor laparotomy, reduced body weight (BW; 10%) transiently (1 week postoperatively). SG reduced BW (10%) for 6 weeks, while DS alone or SG followed by DS led to a continuous BW loss from 15% at 1 week to 50% at 8 weeks postoperatively. Food intake was higher and the satiety ratio was lower during the night than the day for all groups of surgeries. Neither VTPP nor SG had measurable effect on food intake, eating behavior and metabolic parameters. DS reduced daily food intake by more than 50%, which was associated with hypercholecystokinin(CCK)emia, reduced meal size and increased satiety ratio, and increased fecal energy content (measured at 8 weeks).. Weight loss after VTPP, SG, or DS differed in terms of degree, duration, and underlying mechanisms. DS without SG was most effective in the long-term, probably due to hyperCCKemia-induced reduction in food intake and long-limb intestinal bypass-induced malabsorption.

Topics: Anastomosis, Surgical; Animals; Cholecystokinin; Digestive System Surgical Procedures; Duodenum; Energy Metabolism; Feeding Behavior; Gastrectomy; Male; Pylorus; Rats; Vagotomy; Weight Loss

Weight regain after weight loss may not be due primarily to voluntary return to social habits but may be explained by changes in peripheral hormonal signals activating hunger and encouraging feeding behavior.. The objective of this study was to investigate physiologic adaptations to weight loss that may encourage weight regain.. The study had a within-subject repeated-measure design [12 healthy, obese men, 33-64 y, body mass index (in kg/m(2)) 30-46] and was a clinical intervention investigation of circulating metabolites and hunger-satiety responses before and after weight loss. Measures included anthropometry (bioelectrical impedance, body weight, and waist circumference), concentrations of circulating hormones and metabolites [ketone bodies, free fatty acids (FFAs), insulin, leptin, glucose, and cholecystokinin (CCK)], and measures of hunger and satiety at baseline, 8 wk after weight loss with a very-low-energy diet, and 1 wk after weight maintenance.. Weight loss led to a reduction in postprandial CCK secretion (P = 0.016). However, when subjects were ketotic (elevated circulating beta-hydroxybutyrate concentrations), CCK secretion was sustained at concentrations before weight loss. After weight loss, there were reduced postprandial FFA concentrations (P = 0.0005). The presence of ketosis sustained FFA to concentrations before weight loss (P = 0.60).. Rapid weight loss of approximately 10% of initial body weight results in a reduction in postprandial CCK and FFA concentrations.

Topics: Adaptation, Physiological; Adult; Anthropometry; Body Mass Index; Cholecystokinin; Eating; Fatty Acids, Nonesterified; Gastrointestinal Tract; Humans; Hunger; Insulin; Ketone Bodies; Ketosis; Leptin; Male; Middle Aged; Nutritional Physiological Phenomena; Obesity; Peptide Hormones; Postprandial Period; Satiation; Signal Transduction; Weight Loss

Polycystic ovary syndrome (PCOS) is a common condition associated with obesity and with reproductive and metabolic dysfunction. Abnormalities in appetite regulation in PCOS patients may contribute to difficulties in weight management.. We aimed to examine appetite, appetite hormones, and ad libitum food consumption before and after weight loss in overweight women with and without PCOS.. Overweight age- and weight-matched women with (n = 14) and without (n = 14) PCOS undertook an 8-wk energy-restricted diet (5185.3 +/- 141.6 kJ/d). At baseline and study end, subjects consumed a test meal (936 kJ; 25% of energy from protein, 9% from fat, and 67% from carbohydrate). Subjective appetite and circulating glucose, insulin, ghrelin, cholecystokinin, and peptide YY were assessed at 0, 15, 30, 45, 60, 90, 120, and 180 min. A mixed buffet lunch was then offered to assess ad libitum food intake.. Weight loss (4.2 +/- 3.9 kg) did not differ significantly between the 2 groups. Women with PCOS had significantly (P = 0.023) lower ghrelin concentrations before and after weight loss than did women without PCOS. The degree of postprandial ghrelin suppression was lower at weeks 0 (P = 0.048) and 8 (P = 0.069) in women with PCOS than in women without PCOS. There were no significant differences between the 2 groups in appetite responses, buffet consumption, or fasting or postprandial peptide YY and cholecystokinin before or after weight loss.. PCOS was associated with lower fasting ghrelin and a smaller postprandial ghrelin suppression both before and after weight loss but was not associated with other postprandial gut peptides, subjective satiety, or food intake. It is not clear whether appetite regulation is impaired in PCOS.

Topics: Adult; Appetite Regulation; Blood Glucose; Cholecystokinin; Eating; Female; Ghrelin; Homeostasis; Humans; Insulin; Motor Activity; Overweight; Peptide YY; Polycystic Ovary Syndrome; Postprandial Period; Weight Loss

To evaluate the early effect of Roux-en-Y (RYGB) gastric bypass on hormones involved in body weight regulation and glucose metabolism. SIGNIFICANT BACKGROUND DATA: The RYGB is an effective bariatric procedure for which the mechanism of action has not been elucidated yet. Reports of hormonal changes after RYGB suggest a possible endocrine effect of the operation; however, it is unknown whether these changes are the cause or rather the effect of surgically induced weight loss. We speculated that if the mechanism of action of the RYGB involves an endocrine effect, then hormonal changes should occur early after surgery, prior to substantial body weight changes.. Ten patients with a mean preoperative body mass index (BMI) of 46.2 kg/m (40-53 kg/m) underwent laparoscopic RYGB. Six patients had type 2 diabetes treated by oral hypoglycemic agents. Preoperatively and 3 weeks following surgery, all patients were tested for fasting glucose, insulin, glucagon, insulin-like growth factor 1 (IGF-1), leptin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), corticosterone, and neuropeptide Y (NPY).. Changes in mean BMI were rather minimal (43.2 kg/m; P = not significant), but there was a significant decrease in blood glucose (P = 0.005), insulin (P = 0.02), IGF-1 (P < 0.05), leptin (P = 0.001), and an increase in ACTH levels (P = 0.01). The other hormones were not significantly changed by surgery. All the 6 diabetic patients had normal glucose and insulin levels and did not require medications after surgery. The RYGB reduced GIP levels in diabetic patients (P < 0.01), whereas no changes in GIP levels were found in nondiabetics.. Roux-en-Y gastric bypass determines considerable hormonal changes before significant BMI changes take place. These results support the hypothesis of an endocrine effect as the possible mechanism of action of RYGB.

Topics: Adrenocorticotropic Hormone; Adult; Anastomosis, Roux-en-Y; Biomarkers; Blood Glucose; Body Mass Index; Cholecystokinin; Female; Follow-Up Studies; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Humans; Leptin; Male; Middle Aged; Obesity, Morbid; Preoperative Care; Probability; Prospective Studies; Sensitivity and Specificity; Somatomedins; Statistics, Nonparametric; Weight Loss

CCK octapeptide (CCK-8) is released by the gut in response to a meal and acts via CCK(A) receptors on vagal afferents to induce satiety. However, the central neural pathways by which peripheral CCK-8 affects feeding are poorly understood. In the present study, we tested the hypothesis that norepinephrine (NE) is necessary for satiety induced by peripheral CCK-8 by using mice lacking dopamine beta-hydroxylase (Dbh(-/-)), the enzyme responsible for synthesizing NE and epinephrine from dopamine. We found that Dbh(-/-) mice are as responsive to the satiating effects of CCK-8 as their normal littermates.

Topics: Animals; Cholecystokinin; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Feeding Behavior; Female; Food Deprivation; Gene Deletion; Male; Mice; Mice, Knockout; Norepinephrine; Peptide Fragments; Satiety Response; Weight Gain; Weight Loss

A gastric pacemaker has been developed to treat morbid obesity. Patients experience increased satiety, the ability to reduce food intake, and a resultant weight loss. However, the mechanism behind the changed eating behavior in paced patients is still under investigation.. This study was performed on 11 morbidly obese patients (mean BMI, 46.0 kg/m2) treated with gastric pacing. The peripheral blood levels of satiety signals of cholecystokinin (CCK), somatostatin, glucagon-like peptide-1 (GLP-1), and leptin were studied 1 month before gastric pacer implantation, 1 month after implantation, and 6 months after activation of electrical stimulation. Blood samples were drawn 12 hours after fasting and in response to a hypocaloric meal (270 kcal). Patients were followed monthly for vital signs and weight level.. Gastric pacing resulted in a significant weight loss of a mean of 10.4 kg (4.4 BMI units). No negative side effects or complications were observed during the treatment. After activation of the pacemaker, meal-related response of CCK and somatostatin and basal levels of GLP-1 and leptin were significantly reduced (p < 0.05) compared with the tests before gastric pacing. The weight loss correlated significantly with a decrease of leptin levels (R = 0.79, p < 0.01).. Gastric pacing is a novel and promising therapy for morbid obesity. Activation of the gastric pacer was associated with a decrease in plasma levels of CCK, somatostatin, GLP-1, and leptin. More studies are necessary to elucidate the correlations between satiety, weight loss, and digestive neuro-hormone changes.

Topics: Adult; Cholecystokinin; Electric Stimulation Therapy; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Leptin; Male; Obesity, Morbid; Peptides; Satiation; Somatostatin; Stomach; Weight Loss

To investigate the central regulation of food intake by quantifying neuron activation of the nucleus of the solitary tract (NTS) after injection of cholecystokinin (CCK) or food intake in gastrectomized rats.. Total gastrectomy is followed by early satiety, low calorie intake, and weight loss in the majority of patients. The etiology of these effects is unknown. Sixty percent to 70% of patients remain underweight after total gastrectomy, the weight loss averaging 25% of preoperative body weight. About two thirds of gastrectomized patients report early satiety, and about 60% do not reach the recommended daily calorie intake. The NTS is a brain stem center involved in the regulation of food intake; thus, the extent and pattern of neuronal activation provide information on the process involved in the initiation of satiation and the regulation of food intake.. The authors investigated neuronal activation in the NTS using c-fos immunohistochemistry following CCK injection or food intake in healthy control rats, sham-operated control rats, age-matched control rats, weight-matched control rats, and vagotomized or gastrectomized rats.. Neuronal activation in the NTS after CCK injection was significantly decreased 21 days after total gastrectomy, but increased by up to 51% 3 months and by up to 102% 12 months after surgery compared to age-matched unoperated control rats. Neuronal activation in the NTS in response to feeding was markedly increased up to fivefold in gastrectomized rats. This increase was early in onset and sustained, and occurred despite significantly reduced food intake. Administration of MK329, a CCK-A receptor antagonist, significantly reduced the number of postprandially activated neurons in both gastrectomized and control rats.. The early postprandial activation of NTS neurons after total gastrectomy in rats may correspond to early satiety reported by patients, while the sustained activation of NTS neurons after a meal could contribute to a reduced daily calorie intake. These data suggest that a disturbed central regulation of food intake might contribute to early satiety, reduced food intake, and weight loss after total gastrectomy.

Topics: Animals; Appetite Regulation; Cholecystokinin; Devazepide; Eating; Gastrectomy; Genes, fos; Hormone Antagonists; Immunohistochemistry; Male; Rats; Rats, Sprague-Dawley; Solitary Nucleus; Vagus Nerve; Weight Loss

This study was designed to investigate the effect of orexin on anorexia induced by cholecystokinin (CCK),a peripheral satiety signal.. We administered orexin A (0.01-1 nmol/mouse) and CCK-8 (3 nmol/mouse) to mice. Food intake was measured at different time-points: 20 min, 1, 2 and 4 h post-intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administrations.. Intracerebroventricular-administered orexin significantly increased food intake in a dose-dependent manner. The inhibitory effect of i.p.-administered CCK-8 on food intake was significantly negated by the simultaneous i.c.v. injection of orexin in a dose-dependent manner.. Orexin reversed the CCK-induced loss of appetite. Our results indicate that orexin might be a promising target for pharmacological intervention in the treatment of anorexia and cachexia induced by various diseases.

Topics: Analysis of Variance; Animals; Anorexia; Carrier Proteins; Cholecystokinin; Dose-Response Relationship, Drug; Eating; Intracellular Signaling Peptides and Proteins; Mice; Neuropeptides; Orexins; Weight Loss

Topics: Anti-Obesity Agents; Cholecystokinin; Humans; Obesity; Weight Loss

Satiety plays an important role in weight control. The meaning of fasting hormone levels and satiety feelings, and how post-absorptive changes after meals high in carbohydrate regulate appetite remains to be demonstrated.. Prospective metabolic study with 25 non-diabetic obese women at the Energy Metabolism Research Unit of the Department of Nutrition Sciences, University of Alabama at Birmingham. We analyzed fasting and postprandial ratings of hunger-satiety and values of various metabolic parameters (serum glucose and insulin, plasma cholecystokinin, respiratory quotient) during controlled weight loss. The postprandial measures were assessed following a test meal providing 320 kcal and yielding a food quotient of 0.89.. In the fasting state, there was no correlation between hunger-satiety ratings and any of the measured metabolic parameters. Under postprandial conditions, satiety was positively related to glucose (p=0.002) and insulin (p=0.002) responses to the test meal. In multivariate analysis including glucose, insulin, cholecystokinin, hunger-satiety ratings and respiratory quotient, insulin was the only independent predictor of satiety in the postprandial state.. These data suggest an association between the endogenous insulin response and feelings of postprandial satiety. Insulin's satiation properties, which could well be mediated by other hormones, may represent a primary factor of food intake regulation after meals relatively high in carbohydrate.

Topics: Adult; Blood Glucose; Cholecystokinin; Energy Intake; Fasting; Female; Food; Humans; Hunger; Insulin; Middle Aged; Multivariate Analysis; Obesity; Oxygen Consumption; Prospective Studies; Satiation; Weight Loss

Subsequent to total gastrectomy, many patients develop maldigestion and weight loss. The mechanisms that underlie these changes are not known. Therefore, in a prospective study, we have analyzed endocrine and exocrine pancreatic function in patients before and 3 months after total gastrectomy.. In 15 patients (12 male, three female, median age 62.4 yr) undergoing total gastrectomy due to gastric cancer, a direct exocrine pancreatic function test (secretin-cerulein test) was performed. In addition, a standard test meal was given to all patients to study endocrine pancreatic function and the pattern of hormones that influence exocrine pancreatic secretion. In nine patients, both function tests were repeated 3 months after total gastrectomy. Before and at 11 points after the application of the test meal, blood samples were taken for the measurement of glucose, insulin, glucagon, gastrin, pancreatic polypeptide, and cholecystokinin. In addition, a secretin-cerulein test was performed to analyze trypsin, chymotrypsin, amylase, bicarbonate, and the juice volume in the duodenal aspirates.. Three months after total gastrectomy, all patients exhibited severe primary exocrine pancreatic insufficiency. Secretin-cerulein tests revealed that pancreatic juice secretion, trypsin, chymotrypsin, and amylase were significantly reduced by 76%, 89%, 91%, and 72%, respectively, 3 months after total gastrectomy and secretin and cerulein stimulation. Post-operatively, the patients had a pathological glucose tolerance with increased postprandial insulin and glucagon secretion. The baseline and postprandial gastrin and pancreatic polypeptide secretion were significantly decreased after total gastrectomy. In contrast, early postprandial cholecystokinin secretion was significantly increased postoperatively.. After total gastrectomy, patients develop severe primary exocrine pancreatic insufficiency with decreased gastrin, decreased late postprandial pancreatic polypeptide, and increased cholecystokinin levels. These findings may explain why many patients with total gastrectomy have maldigestion and weight loss postoperatively. Therefore, gastrectomized patients should be given pancreatic enzymes to avoid these symptoms.

Topics: Ceruletide; Cholecystokinin; Exocrine Pancreatic Insufficiency; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Malabsorption Syndromes; Male; Middle Aged; Pancreatic Function Tests; Pancreatic Polypeptide; Postgastrectomy Syndromes; Prospective Studies; Secretin; Time Factors; Weight Loss

To determine the cause of body weight loss after total gastrectomy.. We evaluated the acute effect of exogenous cholecystokinin (CCK) on food intake and the chronic effect of CCK receptor blockade on food intake and body weight after total gastrectomy in rats.. Exogenous CCK significantly reduced food intake in gastrectomized rats; this was blocked by administration of a CCK-A but not a CCK-B receptor antagonist. Chronic treatment with a CCK-A or CCK-B receptor antagonist after total gastrectomy in rats significantly increased postoperative food intake and body weight.. Our data indicate that endogenous CCK is partly responsible for reduced food intake and body weight loss after total gastrectomy in rats.

Topics: Animals; Cholecystokinin; Eating; Gastrectomy; Male; Rats; Rats, Sprague-Dawley; Weight Loss

Tolerance to the anorectic effect of dexfenfluramine (DFEN) is shown in rats treated either chronically with low doses or once with a high dose of the agent. Rats given DFEN regimens that result in complete loss of DFEN anorexia showed no change in the anorexia caused by peripheral injection of cholecystokinin (CCK). The orexigenic effects of metergoline and neuropeptide Y were also unaltered as a function of DFEN pretreatment. Both the magnitude and duration of tolerance to a test dose of DFEN seemed to depend, in part, upon contingent (situational) factors, and were independent of whether brain serotonin (5-HT) measures were either unaffected or decreased by the DFEN pretreatment (low and high doses, respectively).

Topics: Animals; Appetite Depressants; Brain; Brain Chemistry; Cholecystokinin; Drug Tolerance; Eating; Female; Fenfluramine; Food Deprivation; Male; Metergoline; Neuropeptide Y; Paroxetine; Rats; Rats, Sprague-Dawley; Serotonin; Weight Loss

Plasma cholecystokinin concentrations were measured with radioimmunoassay in breast fed infants in Sweden (n = 101) and formula fed infants in Italy (n = 119). Blood samples were collected from the infants during the first five postnatal days, just before feeding in a cross-sectional way. We found no significant difference in the hormone concentration in relation to age, in breast fed or in formula fed infants. Breast fed infants had significantly higher plasma hormone concentrations than formula fed infants during the postnatal period 0-5 days: 2.8 pmol/l (1-10 pmol/l), median (range) versus 2.2 pmol/l (1-25 pmol/l), (P < 0.02). It cannot be excluded that the results were influenced by the circumstances that the samples were collected from two separate populations. However, the higher hormone levels in breast fed infants may also be the expression of the fact that natural feeding per se promotes cholecystokinin secretion in newborn infants.

Topics: Breast Feeding; Cholecystokinin; Humans; Infant Food; Infant, Newborn; Weight Loss

Based on a large number of studies in various species, cholecystokinin (CCK) is considered to function as an important regulator of satiety. The present study was undertaken to determine the relationship between hunger score and basal and postprandial plasma CCK secretion, in six obese subjects before and after weight loss with modified fasting. Modified fasting (modifast, 240 kcal/day) for ten weeks induced a mean weight loss of 23 kg. The hunger score was reduced by about 75%. However, basal and plasma CCK release induced by 80 kcal of modifast were not different before and after ten weeks of modifast treatment. Thus, the reduction of hunger during modified fasting is not mediated by circulating CCK.

Topics: Adult; Cholecystokinin; Diet, Reducing; Energy Intake; Female; Humans; Hunger; Male; Obesity; Weight Loss

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental

Topics: Adenoma, Islet Cell; Animals; Anorexia; Base Sequence; Blotting, Northern; Cholecystokinin; Eating; Gastrins; Gene Expression; Glucagon; Hormones; Hypoglycemia; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Precursors; Rats; Tumor Cells, Cultured; Weight Loss