Tanya J. Little

Role of cholecystokinin in appetite control and body weight regulation

Cholecystokinin (CCK), a peptide that is distributed widely throughout the gastrointestinal tract and the central nervous system, has a number of physiological effects including the stimulation of gallbladder contraction and pancreatic and gastric acid secretion, slowing of gastric emptying and suppression of energy intake. This review focuses on current knowledge relating to (i) the effects of CCK on energy intake; (ii) the role for CCK in the pathophysiology of obesity; and (iii) the therapeutic potential for strategies which modulate the action or secretion of CCK in the management of obesity. While CCK plays a role in the acute regulation of appetite and energy intake, there is little evidence to suggest that specific CCK receptor agonists, or modulation of the actions of endogenous CCK by dietary manipulation, have sustainable inhibitory effects on energy intake. Hence, it appears unlikely that manipulating the pathways by which CCK modulates energy intake will prove to be an effective strategy in the long term management of obesity.

Effects of the phases of the menstrual cycle on gastric emptying, glycemia, plasma GLP-1 and insulin, and energy intake in healthy lean women

There is evidence that the menstrual cycle affects appetite, such that energy intake is lower during the follicular compared with the luteal phase. Gastric emptying influences energy intake, glycemia, and plasma glucagon-like peptide-1 (GLP-1), insulin, and cholecystokinin (CCK) release. We hypothesized that 1) gastric emptying of a glucose drink is slower, and glycemia, plasma hormones, hunger, and energy intake are less, during the follicular compared with the luteal phase; 2) the reduction in the latter parameters during the follicular phase are related to slower gastric emptying; and 3) these parameters are reproducible when assessed twice within a particular phase of the menstrual cycle. Nine healthy, lean women were studied on three separate occasions: twice during the follicular phase (days 6-12) and once during the luteal phase (days 18-24). Following consumption of a 300-ml glucose drink (0.17 g/ml), gastric emptying, blood glucose, plasma hormone concentrations, and hunger were measured for 90 min, after which energy intake at a buffet meal was quantified. During the follicular phase, gastric emptying was slower (P < 0.05), and blood glucose (P < 0.01), plasma GLP-1 and insulin (P < 0.05), hunger (P < 0.01), and energy intake (P < 0.05) were lower compared with the luteal phase, with no differences for CCK or between the two follicular phase visits. There were inverse relationships between energy intake, blood glucose, and plasma GLP-1 and insulin concentrations with the amount of glucose drink remaining in the stomach at t = 90 min (r < -0.6, P < 0.05). In conclusion, in healthy women 1) gastric emptying of glucose is slower, and glycemia, plasma GLP-1 and insulin, hunger, and energy intake are less during the follicular compared with the luteal phase; 2) energy intake, glycemia, and plasma GLP-1 and insulin are related to gastric emptying; and 3) these parameters are reproducible when assessed twice during the follicular phase.

Effects of dietary fat on appetite and energy intake in health and obesity — Oral and gastrointestinal sensory contributions

While epidemiological studies have revealed a strong positive relationship between the intake of dietary fat with total energy intake and body weight, laboratory-based studies investigating physiological effects of fat have demonstrated that the direct exposure of receptors in the oral cavity and small intestine to fat, specifically fatty acids (FAs), induces potent effects on gastrointestinal (GI) motility and gut peptide secretion that favor the suppression of appetite and energy intake. Recent studies in humans have demonstrated an association between a decreased ability to detect the presence of FAs in the oral cavity with increased energy intake and body mass index suggesting that impairment of oral fat sensing mechanisms may contribute to overeating and obesity. Furthermore, while sensing of the presence of FAs in the small intestine results in the modulation of GI motility, stimulation of GI hormone release, including cholecystokinin (CCK) and peptide YY (PYY), and suppression of subsequent energy intake, recent data indicate that these effects of fat are attenuated in individuals with reduced oral sensitivity to fat, and following consumption of a high-fat diet. This review will focus on emerging knowledge about the physiological mechanisms that sense the presence of fat in both the oral cavity and the small intestine, and environmental factors, such as high-fat diet exposure and energy restriction, that may modulate sensitivity to nutrients, and thereby contribute to the regulation of appetite and body weight.

The droplet size of intraduodenal fat emulsions influences antropyloroduodenal motility, hormone release, and appetite in healthy males

BACKGROUND The presence of fat in the small intestine modulates gastrointestinal motility, stimulates plasma cholecystokinin and peptide YY release, and suppresses appetite and energy intake. These effects are dependent on the lipolysis of fat. OBJECTIVE Our aim was to evaluate the hypothesis that increasing the droplet size of a fat emulsion would attenuate these effects. DESIGN Ten healthy, lean males were studied on 4 separate occasions in single-blind randomized order. Antropyloroduodenal pressures, plasma triglycerides, cholecystokinin, peptide YY, and appetite were measured during 120-min intraduodenal infusions of fat emulsions comprising 3 different droplet sizes: 1) 0.26 microm (LE-0.26), 2) 30 microm (LE-30), and 3) 170 microm (LE-170) in addition to saline (control). Energy intake at a buffet lunch was quantified immediately after the infusions. RESULTS Increasing the droplet size of the lipid emulsion was associated with diminished suppression of antral (r = 0.75, P < 0.01) and duodenal (r = 0.80, P < 0.01) pressure waves and with stimulation of isolated (r = -0.72, P < 0.01) and basal (r = -0.83, P < 0.01) pyloric pressures. Increasing the droplet size was also associated with attenuation of the stimulation of plasma triglycerides (r = -0.73, P < 0.001), cholecystokinin (r = -0.73, P < 0.001), and peptide YY (r = -0.83, P < 0.001) as well as with reductions in the suppression of hunger (r = 0.75, P < 0.01) and energy intake (r = 0.66, P < 0.001). CONCLUSIONS The acute effects of intraduodenal fat emulsions on gastrointestinal function and appetite are dependent on fat droplet size. These observations have implications for the design of functional foods to maximize effects on those gut functions that are involved in the suppression of appetite.

Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men

BACKGROUND Intraduodenal lipid modulates gastrointestinal motility and hormone release and suppresses energy intake (EI) more than does intraduodenal glucose. Oral protein is the most satiating macronutrient and modulates postprandial glycemia; the comparative effects of intraduodenal protein and lipid and their combined effects are unclear. OBJECTIVE We investigated the effects of intraduodenal protein and lipid, alone or in combination, on antropyloroduodenal motility, gastrointestinal hormone release, glycemia, and EI. DESIGN Twenty lean men were studied on 5 randomized, double-blind occasions. Antropyloroduodenal motility, cholecystokinin, glucagon-like peptide-1 (GLP-1), insulin, glucagon, blood glucose, appetite, and nausea were measured during 90-min isocaloric (3 kcal/min) intraduodenal infusions of lipid [pure lipid condition (L3)], protein [pure protein condition (P3)], a 2:1 combination of lipid and protein [2:1 lipid:protein condition (L2P1)], a 1:2 combination of lipid and protein [1:2 lipid:protein condition (L1P2)], or a control. Immediately after the infusion, EI from a buffet lunch was quantified. RESULTS In comparison with the control, all nutrient infusions suppressed antral and duodenal and stimulated pyloric pressures (P < 0.05). Cholecystokinin and GLP-1 release and pyloric stimulation were lipid-load dependent (r ≥ 0.39, P < 0.01), insulin and glucagon releases were protein-load dependent (r = 0.83, P < 0.001), and normoglycemia was maintained. L3 but not P3 increased nausea (P < 0.05). Compared with the control, L3 and P3 but not L2P1 or L1P2 suppressed EI (P < 0.05) without major effects on appetite. CONCLUSIONS In lean men, despite differing effects on gut function, intraduodenal lipid and protein produce comparable reductions in energy intake. The effects of lipid may be a result of nausea. Protein also regulates blood glucose by stimulating insulin and glucagon. In contrast, at the loads selected, lipid:protein combinations did not suppress energy intake, suggesting that a threshold load is required to elicit effects. This trial was registered at Australia and New Zealand Clinical Trial Registry (http://www.anzctr.org.au) as 12609000949280.

Effects of lauric acid on upper gut motility, plasma cholecystokinin and peptide YY, and energy intake are load, but not concentration, dependent in humans

Animal studies suggest that the effects of fatty acids on gastric emptying and pancreatic secretion are both concentration and load dependent, while their suppressive effect on energy intake is only load dependent. We postulated that, in humans, the modulation of antropyloroduodenal pressure waves, plasma cholecystokinin (CCK) and peptide YY (PYY) concentrations and energy intake by intraduodenal lauric acid, a fatty acid with 12 carbon atoms (‘C12’) would be load, but not concentration, dependent. Two groups of 12 healthy males were each studied on three separate occasions in double‐blind randomized fashion. Antropyloroduodenal pressure waves, plasma CCK and PYY, and appetite perceptions were measured during intraduodenal infusions of C12 at (1) different loads of (i) 0.2, (ii) 0.3 and (iii) 0.4 kcal min−1 (all 56 mm) for 90 min, and (2) different concentrations of (i) 40, (ii) 56 and (iii) 72 mm (all 0.4 kcal min−1) for 60 min. Energy intake at a buffet meal consumed immediately following each infusion was quantified. Suppression of antral and duodenal pressure waves, stimulation of pyloric pressure waves, stimulation of plasma CCK and PYY, and suppression of energy intake, were related to the load of C12 administered (r > 0.65, P < 0.05). In contrast, there were no concentration‐dependent effects of C12 on any of these parameters. In conclusion, in humans, the effects of intraduodenal C12 on antropyloroduodenal motility, plasma CCK and PYY and energy intake appear to be related to load, but not concentration, at least at the loads and concentrations evaluated.

Pooled-data analysis identifies pyloric pressures and plasma cholecystokinin concentrations as major determinants of acute energy intake in healthy, lean men

BACKGROUND The interaction of nutrients with the small intestine modulates gastropyloroduodenal motility, stimulates the release of gut hormones, and suppresses appetite and energy intake. OBJECTIVE We evaluated which, if any, of these variables are independent determinants of acute energy intake in healthy, lean men. DESIGN We pooled data from 8 published studies that involved a total of 67 healthy, lean men in whom antropyloroduodenal pressures, gastrointestinal hormones, and perceptions were measured during intraduodenal nutrient or intravenous hormone infusions. In all of the studies, the energy intake at a buffet lunch was quantified immediately after the infusions. To select specific motor, hormone, or perception variables for inclusion in a multivariable mixed-effects model for determination of independent predictors of energy intake, we assessed all variables for collinearity and determined within-subject correlations between energy intake and these variables by using bivariate analyses adjusted for repeated measures. RESULTS Although correlations were shown between energy intake and antropyloroduodenal pressures, plasma hormone concentrations, and gastrointestinal perceptions, only the peak number of isolated pyloric-pressure waves, peak plasma cholecystokinin concentration, and area under the curve of nausea were identified as independent predictors of energy intake (all P < 0.05), so that increases of 1 pressure wave, 1 pmol/L, and 1 mm . min were associated with reductions in energy intake of approximately 36, approximately 88, and approximately 0.4, respectively. CONCLUSION We identified specific changes in gastrointestinal motor and hormone functions (ie, stimulation of pyloric pressures and plasma cholecystokinin) and nausea that are associated with the suppression of acute energy intake.

Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid

Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

Gastric emptying, mouth-to-cecum transit, and glycemic, insulin, incretin, and energy intake responses to a mixed-nutrient liquid in lean, overweight, and obese males

Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid (r = -0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.

Effects of intraduodenal infusion of L-tryptophan on ad libitum eating, antropyloroduodenal motility, glycemia, insulinemia, and gut peptide secretion in healthy men.

CONTEXT Changes in gut motor and hormonal function contribute to the eating-inhibitory and glucose-lowering effects of protein. The effect of amino acids, the digestive products of protein, on gastrointestinal function, eating, and glycemia has not been investigated comprehensively. OBJECTIVE We tested the hypothesis that L-tryptophan (L-Trp) stimulates gastrointestinal motor and hormonal functions, inhibits eating, and modulates glycemia. Design, Settings, Participants, and Intervention: Ten healthy, normal-weight men were studied in randomized, double-blind fashion, each receiving a 90-minute intraduodenal infusion of L-Trp at 0.075 (total 6.75 kcal) or 0.15 (total 13.5 kcal) kcal/min or saline (control). MAIN OUTCOME MEASURES Antropyloroduodenal motility, plasma ghrelin, cholecystokinin, glucagon-like peptide-1, peptide tyrosine tyrosine, insulin, glucagon, blood glucose, and appetite perceptions were measured. Food intake was quantified from a buffet meal after the infusion. RESULTS Intraduodenal L-Trp suppressed antral pressures (P < .05) and stimulated pyloric pressures (P < .01) and markedly increased cholecystokinin and glucagon (both P < .001). Glucagon-like peptide-1 and peptide tyrosine tyrosine increased modestly (both P < .001), but there was no effect on total ghrelin. Insulin increased slightly (P < .05) without affecting blood glucose. Plasma L-Trp increased substantially (P < .001). All effects were dose-related and associated with increased fullness and substantially decreased energy intake (P < .001). There was a strong inverse correlation between energy intake and plasma L-Trp (r = -0.70; P < .001). CONCLUSIONS Low caloric intraduodenal loads of L-Trp affect gut motor and hormonal function and markedly reduce energy intake. A strong inverse correlation between energy intake and plasma L-Trp suggests that, beyond gut mechanisms, direct effects of circulating L-Trp mediate its eating-inhibitory effect.