Plasma CCK Research Articles

Food temperature altered macronutrients induced changes in satiety hormones; glucagon - like peptide -1 and cholecystokinin and their correlation with subjective satiety.

The benefits of dietary macronutrients for weight management depend on the integrity of gut hormones. The role of food temperature in the release of satiety hormones and satiety needs elucidation. We aimed to determine the impact of different food temperatures with varying macronutrient compositions on satiety-related gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) and find the correlation of satiety hormones with appetite scores and remainder-day food (energy) intake. Thirteen healthy participants (eight males and five females) aged 25-35 years with body mass index 18.5-24.9 kg/m2 with no medical illnesses or eating disorders consumed three compositions of meals (high carbohydrate, high fat, and high protein meals) each at three temperatures (cold, warm, and hot) in a randomized, double-blinded, controlled crossover design. Plasma concentrations of peptide hormones were determined at 0, 30, and 240 minutes by enzyme-linked immunosorbent assay, and 24-hours food recall was used for remainder-day food intake (remainder energy). Data were analyzed using SPSS version 27.0. The change in plasma levels of gut hormones with time was assessed using Friedman test; Kruskal-Wallis test was employed to compare GLP-1 and CCK hormonal levels across nine meals. A comparison of the three meals at the three temperatures (total of nine groups), showed that the GLP-1 and CCK plasma concentrations were significantly different (P < 0.001). GLP-1 and CCK responses increased more after hot meals than cold meals. Overall, high-fat meals had more effective gut hormone secretions. The area under the curve was increased for GLP-1 in high-fat meals and for CCK in hot meals. The peptide hormones (GLP-1 and CCK) were positively correlated with satiety scores and inversely with remainder food intake. The temperature of food was found to be an effective stimulus for the regulation of CCK and GLP-1 secretion. Hot food temperature increased satiety hormones (CCK and GLP-1), independent of food macronutrient composition.

Novel regulation of kidney function by gastrointestinal hormones

The control of whole-body energy metabolism involves intricate crosstalk between multiple organ systems including the gut and the brain that play well-recognized roles in this process. However, the important contributions and mechanisms by other organs are poorly understood. Errors in metabolic regulation can lead to human metabolic diseases including diabetes and obesity that affect 75% of the population and can lead to significant comorbidities. Improving our mechanistic understanding of multi-organ metabolic crosstalk in health and disease is essential for developing highly effcient and new therapeutic approaches. Macula densa (MD) cells in the kidney are chief regulators of renal blood flow and tissue remodeling. We hypothesized that the kidney is a major player in body metabolism via a new mechanism of gut-kidney crosstalk that involves the gut hormones gastrin and cholecystokinine (CCK) activating intrarenal, MD-specific mechanisms to increase blood flow and filtration, progenitor cells and tissue growth factors. High-resolution MD bulk and single-cell transcriptome analysis was performed from freshly isolated, enriched MD cells using MD-GFP mouse kidneys. Single cell MD Ca2+ signaling was analyzed in vivo using intravital multiphoton microscopy (MPM) of Sox2-GT mice that express the ratiometric Ca2+ reporter GCaMP6f/tdTomato in all renal cells. The altered expression of MD specific markers in response to gastrin/CCK8 stimuli was studied using western blot and the novel MDgeo immortalized cell line cultured in vitro. RNA sequencing and transcriptome analysis identified the gastrin/CCK receptor Cckbr as one of the highest expressed genes in MD versus control kidney cells. Intravital multiphoton imaging of Sox2-GCaMP6 reporter mouse kidneys revealed robust and entirely MD cell-specific calcium signaling in response to systemic gastrin/CCK injection. Using the novel MDgeo immortalized cell line cultured in vitro, CCK8 treatment led to 3-fold increases in MD cell synthesis of Prostaglandin E2 (PGE2)-generating COX2 and CCN1 that are established mediators of MD-induced glomerular hyperfiltration and tissue remodeling, respectively. Chronic treatment of Ren1d-Confetti mice with Darunavir, an HIV protease inhibitor significantly increased plasma CCK levels, Ren+ mesenchymal progenitor cell number and clonality, renal cell proliferation and tissue hypertrophy. This study uncovered new regulatory mechanisms of systemic metabolism especially the role of MD cells in the kidney. Repurposing the commonly used HIV drug Darunavir for kidney and metabolic diseases may provide therapeutic benefit for millions of patients worldwide. DK064234, DK123564, DK135290. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Environmental stress during adolescence promotes depression-like behavior and endocrine abnormalities in rats

ObjectiveTo assess the ability of environmental stress (ES) during adolescence on depression-like behaviors and endocrinology in rats. MethodsMale and female Sprague-Dawley rats before or during puberty were divided into three groups: control group (CON), low-frequency ES group (LF), and high-frequency ES group (HF). ES included water/food deprivation and reversal of day and night. After 4 weeks of ES, the behavioral tests were performed. Plasma concentrations of hormones and peptides were determined by enzyme-linked immunosorbent assay (ELISA). ResultsES induced a significant decrease in sucrose preference value in female adolescent rats but not males. In prepubertal rats, the reductions in sucrose preference upon ES were observed without a sex-specific effect. Compared with the CON group, female adolescent rats showed a significant increase, while male adolescent rats showed a significant decrease in plasma corticosterone (CORT) after ES. Also, ES significantly increased plasma leptin in female and male adolescent rats. Moreover, ES significantly increased plasma cholecystokinin (CCK), neuropeptide Y (NPY), and testosterone (TS) levels in adolescent female rats but not in males. No significant differences were found in plasma progesterone and E2 among adolescent rats. The prepubertal male rats showed significant plasma E2 and TS increase after ES, while there were no significant differences between groups in plasma CORT, leptin, CCK, NPY, and progesterone. ConclusionsES may cause depression-like behaviors in adolescent female rats. Our findings supplement the scientific basis for formulating strategies to treat and prevent adolescent depression.

Identification and target of action of cholecystokinin-releasing peptides from simulated digestion hydrolysate of wheat protein.

Wheat protein intake leads to improved appetite control. However, the active components causing appetite in wheat have not been fully clarified. Gut cholecystokinin (CCK) plays a vital role in appetite control. This study aimed to investigate the ability of wheat protein digest (WPD) to stimulate CCK secretion and clarify the active components and target of action. WPD was prepared by a simulated gastrointestinal digestion model. WPD treatment with a concentration of 5 mg mL-1 significantly stimulated CCK secretion in enteroendocrine STC-1 cells (P < 0.05). Furthermore, oral gavage with WPD in mice significantly increased plasma CCK level at 60 min (P < 0.01). Preparative C18 column separation was used to isolate peptide fractions associated with CCK secretion and peptide sequences were identified by liquid chromatography-tandem mass spectrometry. A new CCK-releasing peptide, RYIVPL, that potently stimulated CCK secretion was successfully identified. After pretreatment with a specific calcium-sensing receptor (CaSR) antagonist, NPS 2143, CCK secretion induced by WPD or RYIVPL was greatly suppressed, suggesting that CaSR was involved in WPD- or RYIVPL-induced CCK secretion. The present study demonstrated that WPD has an ability to stimulate CCK secretion in vitro and in vivo, and determined that peptide RYIVPL in WPD could stimulate CCK secretion through CaSR. © 2023 Society of Chemical Industry.

Neprilysin deficiency reduces hepatic gluconeogenesis in high fat-fed mice

Neprilysin is a peptidase that cleaves glucoregulatory peptides, including glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK). Some studies suggest that its inhibition in diabetes and/or obesity improves glycemia, and that this is associated with enhanced insulin secretion, glucose tolerance and insulin sensitivity. Whether reduced neprilysin activity also improves hepatic glucose metabolism has not been explored. We sought to determine whether genetic deletion of neprilysin suppresses hepatic glucose production (HGP) in high fat-fed mice. Nep+/+ and Nep−/− mice were fed high fat diet for 16 weeks, and then underwent a pyruvate tolerance test (PTT) to assess hepatic gluconeogenesis. Since glycogen breakdown in liver can also yield glucose, we assessed liver glycogen content in fasted and fed mice. In Nep−/− mice, glucose excursion during the PTT was reduced when compared to Nep+/+ mice. Further, liver glycogen levels were significantly greater in fasted but not fed Nep−/− versus Nep+/+ mice. Since gut-derived factors modulate HGP, we tested whether gut-selective inhibition of neprilysin could recapitulate the suppression of hepatic gluconeogenesis observed with whole-body inhibition, and this was indeed the case. Finally, the gut-derived neprilysin substrates, GLP-1 and CCK, are well-known to suppress HGP. Having previously demonstrated elevated plasma GLP-1 levels in Nep−/− mice, we now measured plasma CCK bioactivity and reveal an increase in Nep−/− versus Nep+/+ mice, suggesting GLP-1 and/or CCK may play a role in reducing HGP under conditions of neprilysin deficiency. In sum, neprilysin modulates hepatic gluconeogenesis and strategies to inhibit its activity may reduce HGP in type 2 diabetes and obesity.

In vitro gastrointestinal digestion of highland barley protein: identification and characterization of novel bioactive peptides involved in gut cholecystokinin secretion.

The satiety hormone cholecystokinin (CCK) plays an important role in food intake inhibition. Its secretion is regulated by dietary components. The search for bioactive compounds that induce CCK secretion is currently an active area of research. The objective of this study was to evaluate the ability of highland barley protein digest (HBPD) to stimulate CCK secretion in vitro and in vivo and identify the responsible peptide sequences. HBPD was prepared by in vitro gastrointestinal digestion model. Peptides of <1000 Da in HBPD accounted for 82%. HBPD was rich in essential amino acids Leu, Phe and Val, but lack in sulfur amino acids Met and Cys. HBPD treatment at a concentration of 5 mg mL-1 significantly stimulated CCK secretion from enteroendocrine STC-1 cells (P < 0.05). Moreover, oral gavage with HBPD in mice significantly increased plasma CCK level. Chromatographic separation was performed to isolate peptide fractions involved in CCK secretion and peptide sequence was determined by ultra-performance liquid chromatography-tandem mass spectrometry. Two novel CCK-releasing peptides, PDLP and YRIVPL, were pointed out for their outstanding CCK secretagogue activity. This study demonstrated for the first time that HBPD had an ability to stimulate CCK secretion in vitro and in vivo and determined the bioactive peptides exerting CCK secretagogue activity in HBPD. © 2023 Society of Chemical Industry.

Leucine (and lysine) increased plasma levels of the satiety hormone cholecystokinin (CCK), and phenylalanine of the incretin glucagon-like peptide 1 (GLP-1) after oral gavages in pigs.

Excess dietary amino acids (AA) has been associated with reduced feed intake, increased satiation, and extended satiety in pigs. Recent ex vivo studies suggested that satiety peptide cholecystokinin (CCK) and insulinotropic glucagon-like peptide 1 (GLP-1), mediated the anorexigenic or insulinotropic effects of Lys, Glu, Phe, Ile, and Leu. However, the ex vivo model limitations require validation in vivo. The aim of the present study was to assess the effect of orally administered AA in vivo in pigs. It was hypothesized that oral Lys, Ile, and Leu have an anorexigenic effect via CCK, while Glu and Phe have an insulinotropic effect increasing circulating levels of GLP-1. Eight entire male pigs (Landrace × Large White) of 18.23 ± 1.06 kg of body weight were administered an oral gavage of water (control) or a 3 mmol/kg of Glu, Ile, Leu, Lys, Phe, or glucose (positive control for GLP-1 release) following an overnight fasting during 5 consecutive days using an incomplete latin square design. Blood samples were collected from the jugular vein before (-5 min, baseline value) and after the gavage (5, 15, 30, 60 and 90 min) to assess CCK and GLP-1 plasma levels. Pigs administered the oral gavage of Leu (P < 0.05), or Lys (P < 0.1) had increased levels of plasma CCK from 0 to 90 min post-gavage when compared to the control. A strong association (P < 0.001) was observed between GLP-1 plasma levels with Phe intake. The impact was significant starting 30 min post-gavage and was sustained until the end of the experiment (90 min post-gavage). Glucose administration increased GLP-1 early after the intake at the 5 min mark (P < 0.1). A positive correlation (P < 0.05, r = 0.89) driven by the impact of Phe at the 60 to 90 min post-gavage was identified between CCK and GLP-1 indicating feedback mechanisms between proximal and distal small intestine. In conclusion, oral gavages of Leu and Lys increased anorexigenic hormone CCK plasma levels in pigs. Phe caused a significant long-lasting increase in incretin GLP-1 plasma levels. Blood CCK and GLP-1 concentrations in Phe gavaged pigs were positively correlated indicating a potential feedback mechanism between proximal (CCK) and distal (GLP-1) small intestine. The present results are compatible with the known anorexigenic effects of excess dietary Leu and Lys, and the insulinotropic effect of Phe in pigs. These results demonstrate the relevance of accurate feed formulation practices particularly in post weaning pigs.

Serum cholecystokinin levels can be a predictive factor for difficult cholecystectomy: Decreased cholecystokinin receptor levels.

Laparoscopic cholecystectomy (LC) is being performed frequently in general surgery practice. Estimation of difficult cholecystectomy is very important to take precautions against complications. Cholecystokinin (CCK) is an important enzyme for gall-bladder motility. CCK receptor is the target for CCK. Fibrosis and emptying problems of gallbladder are related with difficult cholecys-tectomies. We aimed to evaluate the association between plasma CCK and difficult cholecystectomy and try to explain the mechanism. Prospective cross-sectional study was conducted on a group of patients with cholelithiasis Patients who underwent elective cholecystectomy were classified into easy, difficult and very difficult preoperatively using LC difficulty scores. Pre-operative gallbladder empting ratios were measured by ultrasonography. Serum C-reactive protein, and postprandial serum CCK and pancreas polypeptide levels were measured before the operation. Operation data including operation times, adhesion scores, and complications were collected. Tissue CCK receptor levels and tissue fibrosis scores were obtained. Easy, difficult, and very difficult LC (DLC) groups were consisted of 34, 28, and 8 patients, respectively. Gallbladder emp-tying was 60% in easy LC group, but 15% in very DLC group. Plasma CCK levels in easy group (37.4 pg/ml) were significantly lower than plasma CCK levels of difficult (58.6 pg/ml), and very difficult groups (66.23 pg/ml). Tissue CCK receptor levels of easy, difficult, and very difficult were 372.4, 178.3, and 144.1 ng/100 mg, respectively. Adhesion scores and fibrosis scores of very difficult group were significantly higher than other groups. Operation times were significantly longer in very difficult group. There were two conversions to open in very DLC group (25%). CCK is a reliable parameter for determining the difficulty of LC. Decreased CCK receptor levels with fibrosis of gallbladder are the probably responsible mechanism.

PS-BPB08-3: OFF-TARGET EFFECTS OF SLEEVE GASTRECTOMY ON BLOOD PRESSURE INDEPENDENT OF BODY WEIGHT REDUCTION IN DIET-INDUCED OBESITY RATS: ROLE OF CHOLECYSTOKININ

Objective: Sleeve gastrectomy (SG) is currently the most selected surgical bariatric procedure for weight loss by shrinking the stomach. SG has been reported to improve glucose metabolism by altering gastrointestinal hormones, but the details of why blood pressure improves are not known. The purpose of this study is to elucidate the mechanism of why SG lowers blood pressure in diet induced obese rats. Design and method: Male Sprague Dawley (SD) rats were subjected to surgical [sham operation (SO) or SG] and dietary interventions [fed a normal diet or high fat diet (HFD) ad libitum or pair fed (PF)]. Diet induced obese rats fed 60% HFD for 12 weeks. Systolic blood pressure (SBP), urinary sodium excretion, and gastrointestinal hormones and renin angiotensin system in renal tissue were examined 4 weeks after surgery. In addition, cholecystokinin (CCK) was administered intraperitoneally to SD rats and evaluated for changes in blood pressure and renal tissue renin angiotensin system. Results: Both SG and PF treatments reduced body weight compared with SO. SG exhibited a reduction in SBP compared with PF, which was associated with a reduction in renal renin (536 ± 48.5 U/g kidney and 1385 ± 55.1 U/g kidney, p &lt; 0.01), angiotensin II (Ang II) (48.2 ± 5.8 ng/g kidney and 258.7 ± 16.9 ng/g kidney, p &lt; 0.01), and catechol O methyltransferase (COMT) levels (0.68 ± 0.05 /αtub and 1.34 ± 0.13/αtub, p &lt; 0.01). SG increased plasma CCK levels compared with PF (p &lt; 0.01 for each), whereas GLP1 and PYY were not changed in fasting. SD rats after CCK administration showed decreased SBP (107.7 ± 2.3 mmHg and 118.0 ± 1.8 mmHg, p &lt; 0.01), COMT (0.49 ± 0.04 /GAPDH and 1.11 ± 0.19/GAPDH, p = 0.02), renin (967 ± 71.3 U/g kidney and 1394 ± 90.8 U/g kidney, p &lt; 0.01), and Ang II (598 ± 76.7 ng/g kidney and 874 ± 86.6 ng/g kidney, p = 0.02) in the kidney compared to controls. Conclusions: The SG reduced SBP, at least in part, through suppression of the sympathetic nerve action by elevation of CCK which is followed by suppression of the intrarenal renin angiotensin system. Conclusions: CCK may have a blood pressure lowering effect, and further research is needed to determine whether CCK can be used as a new antihypertensive agent in the future.

Increased Meal Size but Reduced Meal-Stimulated Plasma Cholecystokinin Concentrations in Women With Obesity.

To better understand the physiological basis of obesity in women, we investigated whether obesity or menstrual cycle phase affects laboratory test-meal size or meal-stimulated plasma cholecystokinin (CCK) concentration. Women with healthy weight (body mass index [BMI] of 18.5-24.9 kg/m2, N = 16) or obesity (BMI 30-39.9 kg/m2, N = 20) were tested once in the late-follicular or peri-ovulatory phase (LF/PO) and once in the mid-luteal phase (ML). Meals of ham sandwiches were offered and blood was sampled. Menstrual cycle phases were verified with participants' reports of menses and measurements of progesterone and luteinizing hormone (LH) concentrations. Women with obesity ate significantly larger meals than women with healthy weight, (mean, 711 [95% CI, 402-1013] kJ, P = 0.001, during the LF/PO and 426 [105-734] kJ, P = 0.027, larger during the ML). Women with healthy weight ate smaller meals during LF/PO than ML (decrease, 510 [192-821 kJ], P = 0.008), but women with obesity did not (decrease, 226 [-87-542] kJ, P = 0.15). CCK concentrations 18 to 30 minutes after meal onset were lower in women with obesity than in women with healthy weight during LF/PO (3.6 [3.1-4.1] vs 6.1 [4.5-7.7] pmol/L; P = 0.004), but not during ML, with a significant interaction effect (1.8 [1.2-2.4] pmol/L, P = 0.048). Women with obesity consumed larger meals than women with healthy weight but displayed reduced meal-stimulated plasma CCK concentrations. These data are consistent with the hypothesis that a defect in CCK secretion compromises satiation in obese women and contributes to the development or maintenance of obesity.

Gut peptide changes in patients with obstructive jaundice undergoing biliary drainage: A prospective case control study.

BACKGROUNDBiliary obstruction is a relatively common condition that affects approximately 5 in 1000 people annually. Malnutrition is very common in patients with biliary obstruction and since it is associated with significant morbidity and mortality, it is important to identify factors and mechanisms involved in its development.AIMTo determine the influence of obstructive jaundice on the hormones controlling appetite and nutritive status.METHODSThis was a prospective case control study performed in a tertiary center in Zagreb, Croatia. Patients with biliary obstruction undergoing internal biliary drainage from September 2012 until August 2013 were enrolled. After excluding patients who developed procedure related complications or were lost in the follow-up, out of initial 73 patients, 55 patients were included in the analysis, including 34 with benign and 21 with malignant disease. Meanwhile, 40 non-jaundiced controls were also included. Appetite, nutritional status, and serum ghrelin, cholecystokinin (CCK), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were determined at admission, 48 h and 28 d after internal biliary drainage. Chi square test was used for categorical variables. Continuous variables were analysed for normality by Kolmogorov–Smirnov test and relevant non-parametric (Mann-Whitney, Kruskal-Wallis, and Friedman) or parametric (t-test and analysis of variance) tests were used.RESULTSPatients with obstructive jaundice were significantly malnourished compared to controls, regardless of disease etiology. Plasma ghrelin and CCK levels were significantly higher in patients with obstructive jaundice. Serum bilirubin concentrations were negatively correlated with ghrelin levels and positively correlated with TNF-α, but had no correlation with CCK concentrations. After internal biliary drainage, a significant improvement of nutritional status was observed although serum concentrations of ghrelin, IL-6, and TNF-α remained significantly elevated even 28 d after the procedure. CCK levels in patients without malnutrition remained elevated 28 d after the procedure, but in patients with malnutrition, CCK levels decreased to levels comparable with those in the control group. We have not established any correlation between appetite and serum levels of ghrelin, CCK, IL-6, and TNF-α before and after biliary drainage.CONCLUSIONPossible abnormalities in ghrelin and CCK regulation may be associated with the development of malnutrition during the inflammatory response in patients with biliary obstruction.

Vagal afferent cholecystokinin receptor activation is required for glucagon-like peptide-1-induced satiation.

Peripheral glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are secreted from enteroendocrine cells, and their plasma concentrations increase in response to eating. While the satiating effect of gut-derived CCK on food-intake control is well documented, the effect of peripheral GLP-1 is less clear. There is evidence that native GLP-1 can inhibit food intake only in the fed state but not in the fasting state. We therefore hypothesized that other gut peptides released during a meal might influence the subsequent effect of endogenous GLP-1 and investigated whether CCK could do so. We found that intraperitoneal injection of CCK in food-restricted mice inhibited food intake during the first 30-minute segment of a 1-hour session of ad libitum chow intake and that mice compensated by increasing their intake during the second half of the session. Importantly, this compensatory behaviour was abolished by an intraperitoneal injection of GLP-1 administered following an intraperitoneal injection of CCK and prior to the 1-hour session. In vivo activation of the free fatty acid 1 (FFA1) receptor with orally administered TAK875 increased plasma CCK concentration and, consistent with the effect of exogenous CCK, we found that prior oral administration of TAK875 increased the eating inhibitory effect of peripherally administered GLP-1. To examine the role of the vagus nerve in this effect, we utilized a saporin-based lesioning procedure to selectively ablate the CCK receptor-expressing gastrointestinal vagal afferent neurones (VANs). We found that the combined anorectic effect of TAK875 and GLP-1 was significantly attenuated in the absence of CCK receptor expressing VANs. Taken together, our results indicate that endogenous CCK interacts with GLP-1 to promote satiation and that activation of the FFA1 receptor can initiate this interaction by stimulating the release of CCK.

Suppression of Energy Intake by Intragastric l-Tryptophan in Lean and Obese Men: Relations with Appetite Perceptions and Circulating Cholecystokinin and Tryptophan

Backgroundl-Tryptophan reduces energy intake in healthy men. The underlying mechanisms, including appetite, plasma cholecystokinin (CCK), tryptophan (Trp), and the ratio of Trp to large neutral amino acids (Trp:LNAAs ratio), and whether responses differ in lean and obese individuals, are uncertain. ObjectivesWe evaluated the effects of intragastric Trp on energy intake (primary outcome) and their potential mechanisms, pre- and postmeal, in lean men and those with obesity. MethodsTwelve lean men [mean ± SD age: 30 ± 3 y; BMI (in kg/m2): 23 ± 1] and 13 men with obesity (mean ± SD age: 31 ± 3 y; BMI: 33 ± 1) received, on 3 separate occasions, in double-blind, randomized order, 3 g (“Trp-3”) or 1.5 g (“Trp-1.5”) Trp, or control (“C”), intragastrically, 30 min before a buffet-meal. Energy intake from the buffet-meal, hunger, fullness, and plasma CCK and amino acid concentrations were measured in response to Trp alone and for 2 h postmeal. Data were analyzed using maximum likelihood mixed-effects models, with treatment, group, and treatment-by-group interaction as fixed effects. ResultsTrp alone increased plasma CCK, Trp, and the Trp:LNAAs ratio (all P < 0.001), with no difference between groups. Trp suppressed energy intake (P < 0.001), with no difference between groups (lean, C: 1085 ± 102 kcal, Trp-1.5: 1009 ± 92 kcal, Trp-3: 868 ± 104 kcal; obese, C: 1249 ± 98 kcal, Trp-1.5: 1217 ± 90 kcal, Trp-3: 1012 ± 100 kcal). Postmeal, fullness was greater after Trp-3 than after C and Trp-1.5 (all P < 0.05), and in men with obesity than in lean men (P < 0.05). Plasma Trp and the Trp:LNAAs ratio were greater after Trp-3 and Trp-1.5 than after C (all P < 0.001), and tended to be less in men with obesity than in the lean (P = 0.07) (Trp:LNAAs ratio: lean, C: 1.5 ± 0.2, Trp-1.5: 6.9 ± 0.7, Trp-3: 10.7 ± 1.4; obese, C: 1.4 ± 0.1, Trp-1.5: 4.6 ± 0.7, Trp-3: 7.8 ± 1.3). There were inverse correlations of energy intake with plasma Trp and the Trp:LNAAs ratio in both groups (lean, both r = −0.50, P < 0.01; obese, both r = −0.40, P < 0.05). ConclusionsIntragastric Trp has potent energy intake–suppressant effects, in both lean men and those with obesity, apparently related to the Trp:LNAAs ratio.

Hypoxia transactivates cholecystokinin gene expression in 3D-engineered muscle

At high altitudes, the hypoxic atmosphere decreases the oxygen partial pressure in the body, inducing several metabolic changes in tissues and cells. Furthermore, it exerts potent anorectic effects, thus causing an energy deficit. Two decades ago, a marked increase in the resting level of plasma cholecystokinin (CCK) was observed in humans at the Mt. Kanchenjunga basecamp, located at 5100m above the sea level, compared to sea-level control values. Interestingly, acute exercise also raises plasma CCK and exerts potent anorectic effects under normoxic conditions. However, the transcriptional regulations of Cck gene underlying these effects have not yet been established. Here, we employed acute electrical pulse stimulation (EPS) followed by microarray analysis to discover novel myokines in 3D-engineered muscle. Acute EPS affects the contractile function, inducing a decline in the contractile force. Surprisingly, microarray analysis revealed an EPS-induced activation of cholecystokinin receptor (CCKR)-mediated signaling. Furthermore, Cck was constitutively upregulated in 3D-engineered muscle, and its expression increased under hypoxic conditions. Notably, a hypoxia-responsive element was detected in the Cck promoters of mice and humans. Our results suggested that hypoxia transactivated Cck expression in 3D-engineered muscle. Furthermore, the elevation in plasma CCK levels following acute exercise or at high altitude might be partly attributed to myogenic cells.

Post-oral fat-induced satiation is mediated by endogenous CCK and GLP-1 in a fat self-administration mouse model

Triacylglycerol is the most abundant dietary lipid, and a strong stimulator of satiation. Absorption of triacylglycerol in the small intestine occurs in the form of free fatty acids and 2-monoacylglycerol, a process known to trigger not only the release of cholecystokinin (CCK) but also glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). It remains controversial, however, whether endogenously released GLP-1 and PYY are required for fat-induced satiation. Using a self-administration model where mice are trained to self-administer Intralipid 30% intragastrically, we show that blocking the CCK1 receptors with intraperitoneal devazepide diminishes the post-oral satiation effect of ingested fat. Similarly, s.c. administration of a GLP-1 receptor antagonist with a prolonged half-life (Jant4-C16) also reduced the post-oral satiation effect of ingested fat. Importantly, coadministration of the GLP-1 antagonist together with devazepide increased fat self-infusions to a level equal to the combined blockade of each individual peptide action alone, indicating an additive effect of endogenous CCK and GLP-1 in fat satiation signaling. Blocking the PYY Y2 receptor did not further enhance the fat intake in devazepide-treated mice. Consistent with the above, we show that voluntary post-oral ingestion of fat increases CCK and GLP-1 plasma levels and is correlated positively with CCK and GLP-1 plasma concentrations. Taken together, our results support the role of endogenous GLP-1 in the regulation of fat intake and suggest that both CCK and GLP-1 are required for the fat satiation signaling.

Correlations between sol viscosity of the partially degraded konjac glucomannan and appetite response of rats

Understanding the correlations between dietary fibers' physical properties and postprandial appetite response helps to design novel functional products with satiety enhancing capability. In the present study, the partially degraded konjac glucomannan (Pd-KGM) was obtained by applying the heterogeneous hygrothermal degradation method, and its flow behavior was studied for guiding the preparation of sols with equi-concentration but differed in viscosity. The appetite-regulating effects derived from the sol viscosity were explored by monitoring the appetite hormone response and the feeding behavior of rats after they were given the Pd-KGM sols. By lowering the secretion of ghrelin, elevating the plasma concentration of GLP-1, PYY3–36, and CCK-8, and stabilizing blood glucose and insulin fluctuation, the sol with increased viscosity showed an improved satiety-enhancing capability. Moreover, the transition point from feeding to resting was advanced in rats given a more viscous sol, resulting in a significantly decreased feed intake (p < 0.05). We further explored the correlations between sol viscosity and its nutritional effects relating to appetite regulation depending on the quantitative data obtained in this study. Excluding the plasma glucose and CCK-8, a strong linear correlation (Pearson coefficient > 0.7) emerged between the appetite hormone and the sol viscosity, especially for the GLP-1, which its Pearson coefficient was 0.946, indicating a very highly correlated relationship between them. Thus, these results revealed the feasibility of regulating appetite by taking advantage of sol viscosity.

Pancreatobiliary Diversion in the Mouse

The gut hormone cholecystokinin (CCK) is primarily secreted from I-cells in the duodenum and proximal jejunum. CCK secretion is stimulated by food digests and inhibited by proteases from pancreatic juice. CCK regulates digestion and appetite, stimulates pancreatic growth, and participates in pancreatic carcinogenesis. The molecular mechanisms of CCK-induced effects are not fully understood. When the mechanisms are studied in animals, the surgical model of pancreatobiliary diversion (PBD) is frequently used. After animals have had PBD, their CCK secretion is no longer inhibited by pancreas-derived proteases, so circulating CCK is increased. PBD is established in rats and hamsters, but not in mice. In this study, we modified PBD procedures and established the model in the mouse. In an experiment, we performed PBD and sham operation (SO) in two groups of mice (20 mice per group). Twenty days after operation, 75% of the PBD mice and all SO mice survived. When plasma CCK was determined by radioimmunoassay, the PBD group had higher levels than the SO group (p < 0.001). To assess pancreatic growth, we determined pancreatic weight and pancreatic contents of protein and DNA. We also stained pancreatic sections by immunohistochemistry to show the proliferating cells that either expressed the proliferating cell nuclear antigen or were labeled with 5-bromo-2′-deoxyuridine. As a result, the pancreases of the PBD mice were heavier (p < 0.001) and had more protein (p < 0.001), DNA (p < 0.01), and proliferating cells (p < 0.01) than those of the SO counterparts. Thus, pancreatic growth was increased as a result of PBD-induced hypercholecystokininemia. The plasma and pancreatic data demonstrated that the PBD model was a success. This model may be used in CCK-related research. For instance, pancreatic cancer is frequently studied in transgenic mice. PBD may be combined with the cancer model to study the role of CCK in the molecular biology of pancreatic cancer.

Circadian variations in plasma concentrations of cholecystokinin and gastrin in man

Cholecystokinin (CCK) is a gut hormone which regulates gallbladder contraction and pancreatic enzyme secretion. In addition, CCK is also a major intestinal satiety signal. The knowledge about CCK in circulation, however, has been limited by difficulties in accurate measurement of the concentrations in plasma. Thus, CCK circulates in low concentrations and furthermore, it is structurally homologous to the antral hormone, gastrin, which circulates in higher concentrations. Therefore, most antibodies raised against CCK cross-react in immunoassays with gastrin. However, using highly sensitive and entirely specific in-house radioimmunoassays, which meet these challenges, we have now measured the daily concentration-variations of CCK and gastrin in plasma from young healthy men (n = 24). Plasma was sampled every third hour from each person during 24 h. The results show that the gastrointestinal secretion of both CCK and gastrin in man display significant circadian variations.

Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma.

Human studies have demonstrated that physiologically relevant changes in circulating glucagon‐like peptide‐1 (GLP‐1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut‐kidney axis, responsible for a rapid‐acting feed‐forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP‐1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12‐hr fasting period. Arterial blood samples were collected at 10–20‐min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty‐four‐hour baseline urinary sodium excretions were similar between study days. Arterial GLP‐1 levels increased during both oral glucose loads and were significantly higher at the 40–80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose‐dependent insulinotropic polypeptide as well as glucose, insulin, and C‐peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP‐1 was higher (60–80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP‐1 plasma concentration. Thus, GLP‐1 may be part of an acute feed‐forward mechanism for natriuresis.

The relationship between cholecystokinin secretion and pancreatic [11C]methionine uptake in patients after partial pancreaticoduodenectomy.

The pancreatic uptake of [11C]methionine ([11C]MET) is associated with beta-cell function and insulin secretion, but [11C]MET uptake and its relationship with exocrine pancreatic performance are less well studied. The postprandial release of cholecystokinin (CCK) depends on gastric emptying velocity and triggers exocrine pancreas secretion. Therefore, we assumed that high postprandial CCK concentrations stimulate the uptake of [11C]MET in the residual pancreas following pancreaticoduodenectomy. Nineteen tumor-free patients after pancreaticoduodenectomy (median age: 64; 25/75 quantile: 56-67years); ten males, nine females and ten healthy controls (median age: 24; 25/75 quantile: 23.8-26years) were given a mixed meal. Plasma CCK, insulin and glucose concentrations were measured before and at 10, 20, 30, 60, 90, 150 and 180min after ingestion. Simultaneously, 800MBq of [11C]MET were administered and the activity [maximum tissue standardized uptake values (SUVmax)] over the pancreas was measured using PET-CT at 15, 30 and 60min after injection. Integrated CCK (AUC30) correlated with SUVmax (AUC60, R2 = 0.45, p value = 0.0013). Multivariate analysis revealed postprandial insulin (AUC60) and CCK concentrations and young age as significant independent predictors of [11C] methionine uptake. The association between CCK concentrations and pancreatic [11C]MET uptake might indicate a causal relationship. Further research should assess whether [11C]MET uptake could serve as a less invasive tool to assess exocrine pancreas activity.