Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people.

There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.

NUTRALYS(®) pea protein: characterization of in vitro gastric digestion and in vivo gastrointestinal peptide responses relevant to satiety.

BACKGROUND: Pea protein (from Pisum sativum) is under consideration as a sustainable, satiety-inducing food ingredient. OBJECTIVE: In the current study, pea-protein-induced physiological signals relevant to satiety were characterized in vitro via gastric digestion kinetics and in vivo by monitoring post-meal gastrointestinal hormonal responses in rats. DESIGN: Under in vitro simulated gastric conditions, the digestion of NUTRALYS(®) pea protein was compared to that of two dairy proteins, slow-digestible casein and fast-digestible whey. In vivo, blood glucose and gastrointestinal hormonal (insulin, ghrelin, cholecystokinin [CCK], glucagon-like peptide 1 [GLP-1], and peptide YY [PYY]) responses were monitored in nine male Wistar rats following isocaloric (11 kcal) meals containing 35 energy% of either NUTRALYS(®) pea protein, whey protein, or carbohydrate (non-protein). RESULTS: In vitro, pea protein transiently aggregated into particles, whereas casein formed a more enduring protein network and whey protein remained dissolved. Pea-protein particle size ranged from 50 to 500 µm, well below the 2 mm threshold for gastric retention in humans. In vivo, pea-protein and whey-protein meals induced comparable responses for CCK, GLP-1, and PYY, that is, the anorexigenic hormones. Pea protein induced weaker initial, but equal 3-h integrated ghrelin and insulin responses than whey protein, possibly due to the slower gastric breakdown of pea protein observed in vitro. Two hours after meals, CCK levels were more elevated in the case of protein meals compared to that of non-protein meals. CONCLUSIONS: These results indicate that 1) pea protein transiently aggregates in the stomach and has an intermediately fast intestinal bioavailability in between that of whey and casein; 2) pea-protein- and dairy-protein-containing meals were comparably efficacious in triggering gastrointestinal satiety signals.

Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression.

Plasma levels of the orexigenic hormone ghrelin are suppressed by meals with an efficacy dependent on their macronutrient composition. We hypothesized that heterogeneity in osmolarity among macronutrient classes contributes to these differences. In three studies, the impact of small intestinal hyperosmolarity was examined in Sprague-Dawley rats. In study 1, isotonic, 2.5×, and 5× hypertonic solutions of several agents with diverse absorption and metabolism properties were infused duodenally at a physiological rate (3 ml/10 min). Jugular vein blood was sampled before and at 30, 60, 90, 120, 180, 240, and 300 min after infusion. Plasma ghrelin was suppressed dose dependently and most strongly by glucose. Hyperosmolar infusions of lactulose, which transits the small intestine unabsorbed, and 3-O-methylglucose (3-O-MG), which is absorbed like glucose but remains unmetabolized, also suppressed ghrelin. Glucose, but not lactulose or 3-O-MG, infusions increased plasma insulin. In study 2, intestinal infusions of hyperosmolar NaCl suppressed ghrelin, a response that was not attenuated by coinfusion with the neural blocker lidocaine. In study 3, we reconfirmed that the low-osmolar lipid emulsion Intralipid suppresses ghrelin more weakly than isocaloric (but hypertonic) glucose. Importantly, raising Intralipid's osmolarity to that of the glucose solution by nonabsorbable lactulose supplementation enhanced ghrelin suppression to that seen after glucose. Hyperosmolar ghrelin occurred particularly during the initial 3 postinfusion hours. We conclude that small intestinal hyperosmolarity 1) is sufficient to suppress ghrelin, 2) may combine with other postprandial mechanisms to suppress ghrelin, 3) might contribute to altered ghrelin regulation after gastric bypass surgery, and 4) may inform dietary modifications for metabolic health.

CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation.

Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study 1, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmol/kg) or vehicle before a 4-h test-food presentation. At most doses, both CCK-8 and CCK-58 similarly reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9 nmol/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 min after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK's role in food intake regulation may require re-examination.

Dietary galacto-oligosaccharides and calcium: effects on energy intake, fat-pad weight and satiety-related, gastrointestinal hormones in rats.

Galacto-oligosaccharides (GOS) are carbohydrates that are fermented by colonic microbiota. The present study examined effects of a 3-week dietary enrichment with 6 % (w/w) GOS on parameters of energy balance in forty-three male Wistar rats. GOS was tested with two doses of calcium phosphate (30 and 100 mmol/kg), known to differently affect colonic fermentation. After 17 d, isoenergetic test meals were presented and plasma responses of ghrelin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured. On day 21 (study termination) epididymal fat pads and caecum were weighed. Additionally, gastrointestinal mucosal samples and proximal colonic contents were analysed for gene expression (ghrelin, proglucagon and PYY) and fermentation metabolites (SCFA and lactate), respectively. GOS reduced energy intake most prominently during the first week, without provoking compensatory overeating later on (average intake reduction: 14 %). The GOS-fed rats showed increased caecal and reduced fat-pad weight and increased gene expression of the satiety-related peptides, PYY (1.7-fold) and proglucagon (3.5-fold). Pre-meal baseline and post-meal plasma levels of PYY, but not of ghrelin or GLP-1, were higher in GOS-fed rats than in control rats. Ca enrichment resulted in higher energy intake (average 4.5 %). GOS diets increased lactic acid levels and slightly reduced butyric acid in proximal colonic contents. Ca abolished the GOS-related elevation of lactic acid, while increasing propionic acid levels, but did not inhibit GOS-related effects on energy intake, fat-pad weight or gene expression. These results indicate that dietary GOS stimulate a number of physiological mechanisms that can reduce energy intake, regardless of the calcium phosphate content of the diet.

Ghrelin increases the motivation to eat, but does not alter food palatability.

Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

Dietary factors affect food reward and motivation to eat.

The propensity to indulge in unhealthy eating and overconsumption of palatable food is a crucial determinant in the rising prevalence of obesity in today's society. The tendency to consume palatable foods in quantities that exceed energy requirements has been linked to an addiction-like process. Although the existence of 'food addiction' has not been conclusively proven, evidence points to alterations in the brain reward circuitry induced by overconsumption of palatable foods that are similar to those seen in drug addiction. The diet-induced obesity paradigm is a common procedure to replicate features of human obesity in rodents. Here we review data on the effect of various obesogenic diets (high-fat, Ensure™, cafeteria type, sucrose) on the extent of leptin resistance, hypothalamic-neuropeptidergic adaptations and changes in feeding behavior. We also discuss to what extent such diets and properties such as macronutrient composition, physical structure, sensory stimuli, and post-ingestive effects influence the brain-reward pathways. Understanding the interaction between individual components of diets, feeding patterns, and brain reward pathways could facilitate the design of diets that limit overconsumption and prevent weight gain.

Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates.

CONTEXT: Ghrelin is an orexigenic hormone that can increase body weight. Its circulating levels increase before meals and are suppressed after food ingestion. Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets. OBJECTIVE: We sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins. DESIGN: This was a randomized, within-subjects cross-over study. SETTING: The study was conducted at a University Clinical Research Center. PARTICIPANTS: There were 16 healthy human subjects included in the study. INTERVENTIONS: Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided. MAIN OUTCOME MEASURES: The magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined. RESULTS: All beverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone. CONCLUSIONS: These findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.

Gastrointestinal regulation of food intake.

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.

Ghrelin and energy balance: focus on current controversies.

Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation--a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a "saginary" hormone, from the Latin, saginare, which means, "to fatten".

Roles for ghrelin in the regulation of appetite and body weight

Purpose of review: Ghrelin, the only known circulating appetite stimulant, has garnered widespread scientific interest and is currently featured in more than 2.3 new publications per day. Antagonists and agonists of its receptor are vigorously being developed by pharmaceutical companies to treat obesity and wasting conditions respectively. Here, the authors summarize the current state of knowledge regarding ghrelin's roles in energy homeostasis. Recent findings: Ghrelin is an acylated peptide produced primarily by the stomach and proximal small intestine. Circulating levels sharply increase before, and decrease after, meals. These and other findings implicate ghrelin in pre-meal hunger and meal initiation. Moreover, ghrelin satisfies established criteria for an adiposity-associated hormone involved in long-term body weight regulation. Blood levels correlate with energy stores and display compensatory changes in response to alterations of those stores. Ghrelin influences neuronal activity in brain areas critical to energy homeostasis. Excessive ghrelin signaling durably increases food intake and decreases energy expenditure, thereby promoting weight gain. Conversely, acute ghrelin blockade in adult animals reduces food intake and body weight, although the effects of lifelong genetic deletions are very subtle. Overproduction of ghrelin is etiologically implicated in Prader-Willi syndrome, whereas defective secretion may contribute to weight loss after gastric bypass surgery. Summary: Ghrelin appears to participate in mealtime hunger and meal initiation, as well as in long-term energy balance. Whether these roles are sufficiently important that ghrelin blockade will prove to be an effective antiobesity modality is a pivotal question that should soon be answered as ghrelin receptor antagonists are developed. Ghrelin agonists hold promise in the treatment of wasting conditions, for which few medications currently exist.

Role of the duodenum and macronutrient type in ghrelin regulation.

The orexigenic hormone ghrelin is implicated in preprandial hunger and meal initiation in part because circulating levels increase before meals and decrease after food intake. The mechanisms underlying postprandial ghrelin suppression are unknown. Although most ghrelin is produced by the stomach, we have shown that neither gastric nutrients nor gastric distension affect ghrelin levels. We hypothesized that the nutrient-sensing mechanism regulating ghrelin is in the duodenum, the second richest source of ghrelin. To test whether duodenal nutrient exposure is required for ghrelin suppression, we infused nutrients into either the proximal duodenum or proximal jejunum in rats bearing chronic intestinal cannulas. At 0, 30, 60, 90, 120, 180, 240, and 300 min after infusions, blood was sampled via jugular-vein catheters for ghrelin, insulin, and glucose measurements. To elucidate further the mechanisms governing nutrient-related ghrelin suppression, we also assessed the ghrelin responses to isocaloric (3 kcal) infusions of glucose, amino acids, or lipids delivered into the stomach or small intestine of chronically catheterized rats. Regardless of macronutrient type, the depth and duration of ghrelin suppression were equivalent after gastric, duodenal, and jejunal infusions. Glucose and amino acids suppressed ghrelin more rapidly and strongly (by approximately 70%) than did lipids (by approximately 50%). Because jejunal nutrient infusions suppressed ghrelin levels as well as either gastric or duodenal infusions, we conclude that the inhibitory signals mediating postprandial ghrelin suppression are not derived discretely from either the stomach or duodenum. The relatively weak suppression of ghrelin by lipids compared with glucose or amino acids could represent one mechanism promoting high-fat dietary weight gain.

Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding.

Plasma levels of the orexigenic hormone, ghrelin, decrease rapidly on nutrient ingestion and yet are paradoxically elevated in rats with hyperphagia induced by streptozotocin-induced diabetes (STZ-DM). In the current work, we investigated the mechanisms underlying the relationships among uncontrolled diabetes, food intake, and plasma ghrelin concentrations in an effort to clarify whether increased ghrelin signaling contributes to diabetic hyperphagia. Whereas food intake did not increase until d 3 after STZ administration, plasma ghrelin levels were increased by more than 2-fold (P < 0.05) on d 1. As hyperphagia developed, however, plasma ghrelin levels declined steadily. Because this reduction of plasma ghrelin levels was reversed by matching food intake of STZ-DM rats to that of nondiabetic controls, our results demonstrated that the effect of uncontrolled diabetes to increase plasma ghrelin levels is partially offset by hyperphagic feeding. In addition, we found that although intragastric nutrient infusion rapidly and comparably decreased plasma ghrelin levels in both groups (by 46-49%; P < 0.05), this effect was short lived in STZ-DM rats relative to nondiabetic controls (60 min vs. 120 min; P < 0.05). We further demonstrated that in rats with STZ-DM, food intake increased by 357% (P < 0.05) in response to intracerebroventricular administration of ghrelin at a dose that was subthreshold for feeding effects in nondiabetic controls. Collectively, these findings demonstrate that uncontrolled diabetes increases both circulating ghrelin levels and behavioral sensitivity to ghrelin. Although plasma ghrelin levels fall in response to hyperphagic feeding, these findings support the hypothesis that increased ghrelin signaling contributes to the pathogenesis of diabetic hyperphagia.

Food Cue Reactivity in Fasting and Non-Fasting Subjects.

In the present study, psychophysiological food cue reactivity was studied in fasting and non-fasting subjects. It was expected that food related stimuli would elicit stronger responses than control (soap) stimuli and that responses to food stimuli would be particularly strong in fasting subjects. The results show that although the subjects' craving was larger during presentation of food cues than during control stimuli, the larger craving was not reflected in increased psychophysiological responsivity (heart rate; frequency of skin conductance (SC) fluctuations) or salivation. Subjects in the fasting condition had a lower baseline frequency of SC-fluctuations, and a trend towards lower heart rate, indicating decreased sympathetic tonic level. In comparison with non-fasting subjects, no specifically enlarged food cue reactivity was found in fasting subjects. It is proposed that future research into food cue reactivity should focus on the role of learning rather than deprivation.