Ghrelin Responses Research Articles

Mechanosensing by Piezo1 in gastric ghrelin cells contributes to hepatic lipid homeostasis in mice.

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell-specific deficiency of Piezo1 (Ghrl-Piezo1-/-) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1-/- mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1-/- mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.

Anti-Obesity Effects of a Collagen with Low Digestibility and High Swelling Capacity: A Human Randomized Control Trial.

Collagen is a protein formed by very long amino acid chains. When conveniently treated, it can incorporate water into the net, thus increasing its volume and mass. The present work aimed to evaluate the potential anti-obesity effects of bovine collagen that has been technologically treated to increase its water retention capacity in an acid pH medium, with the objective of inducing satiation. Collagen's digestibility was tested with a pepsin digestion test. Its swelling capacity was tested in an acid pH medium simulating gastric conditions. Postprandial levels of ghrelin in response to collagen supplementation were tested in rats. In a randomized control trial, 64 subjects with overweight/obesity were allocated in two groups: supplemented daily with two protein bars enriched with collagen (20 g per day) for 12 weeks, or control group. Anthropometric and biochemical measurements were assessed in all the participants. This collagen showed a low digestibility (<60%) and high swelling capacity (>1900%) in vitro. In humans with overweight and obesity, this collagen significantly reduced body weight, body mass index (BMI), systolic blood pressure (SBP), and fatty liver index (FLI) and increased fat-free mass when compared with the control group. A significant reduction in the sarcopenic index; total, troncular, and visceral fat (measured by DEXA); and serum leptin levels were observed in the collagen group at the end of the intervention, with no differences with respect to controls. Collagen reduced the sensation of hunger and increased fullness and satisfaction. In male Wistar rats, collagen decreased postprandial blood ghrelin levels. Collagen supplementation (20 g per day for 12 weeks) reduced body weight, BMI, waist circumference, fat mass, FLI, and SBP in humans with overweight and obesity, which might be related to the increased sensation of fullness and satisfaction reported by the volunteers after the intake.

Evaluating the impact of metabolic and cognitive stress on ghrelin and nesfatin-1 hormones in patients with diabetes and diabetic depression.

Nesfatin-1 and ghrelin, initially recognised as hormones involved in regulating energy, have emerged as crucial players with vital functions in various human body systems. In this study, we conducted a comparative assessment of nesfatin-1 and ghrelin responses in individuals experiencing metabolic stress due to diabetes, those with depressive diabetes characterised by both metabolic and mental stress, and healthy controls. We collected blood samples from a total of 90 participants, consisting of 30 people with type II diabetes mellitus (DM), 30 people with type II DM and major depressive disorders, and 30 healthy individuals. Diabetes was diagnosed based on glycated haemoglobin (HbA1c) levels, while depression was assessed using DSM-V criteria. Insulin resistance (HOMA-IR) was calculated, and serum ghrelin and nesfatin-1 levels were measured using ELISA kits. We observed statistically significant decreases in nesfatin-1 and ghrelin levels in the diabetic group (p<0.0001). However, in the depressive diabetic group, nesfatin-1 levels increased significantly, while ghrelin levels decreased further. The nesfatin-1 to ghrelin ratio decreased in the diabetic group but increased significantly in the depressive diabetic group (p<0.0001). Nesfatin-1 and ghrelin hormones exhibit parallel impacts in response to metabolic stress, but nesfatin-1 demonstrates contrasting actions compared to ghrelin when mental stress is added to metabolic stress. The findings of this study suggest that nesfatin-1 and ghrelin hormones may play active roles as protective, prognostic, and even etiological factors in various stress situations, particularly those involving mental stress, in addition to their known functions in regulating energy.

Effects of Wheat Biscuits Enriched with Plant Proteins Incorporated into an Energy-Restricted Dietary Plan on Postprandial Metabolic Responses of Women with Overweight/Obesity.

This study investigates the effect of daily consumption of wheat biscuits enriched with plant proteins in postprandial metabolic responses of women with overweight/obesity who follow an energy-restricted diet. Thirty apparently healthy women participated in a 12-week randomized controlled trial and were assigned either to a control (CB) or an intervention (PB) group. Participants consumed daily either a conventional (CB) or an isocaloric wheat biscuit enriched with plant proteins (PB) containing high amounts of amino acids with appetite-regulating properties, i.e., BCAAs and L-arg. At baseline and the end of the intervention, a mixed meal tolerance test was performed. The responses of glucose, insulin, ghrelin, GLP-1, and glicentin were evaluated over 180 min. After 12 weeks, both groups experienced significant decreases in body weight, fat mass, and waist circumference. In the PB group, a trend towards higher weight loss was observed, accompanied by lower carbohydrate, fat, and energy intakes (p < 0.05 compared to baseline and CB group), while decreases in fasting insulin and the HOMA-IR index were also observed (p < 0.05 compared to baseline). In both groups, similar postprandial glucose, ghrelin, and GLP-1 responses were detected, while iAUC for insulin was lower (p < 0.05). Interestingly, the iAUC of glicentin was greater in the PB group (p < 0.05 compared to baseline). Subjective appetite ratings were beneficially affected in both groups (p < 0.05). Consumption of wheat biscuits enriched in plant proteins contributed to greater weight loss, lower energy intake, and insulin resistance and had a positive impact on postprandial glicentin response, a peptide that can potentially predict long-term weight loss and decreased food intake.

Differential changes in appetite hormones post-prandially based on menstrual cycle phase and oral contraceptive use: A preliminary study

This was a preliminary study that examined whether appetite regulation is altered during the menstrual cycle or with oral contraceptives. Ten naturally cycling females (NON-USERS) and nine tri-phasic oral contraceptive using females (USERS) completed experimental sessions during each menstrual phase (follicular phase: FP; ovulatory phase: OP; luteal phase: LP). Appetite perceptions and blood samples were obtained fasted, 30, 60, and 90 min post-prandial to measure acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and total peptide tyrosine tyrosine (PYY). Changes were considered important if p < 0.100 and the effect size was ≥medium. There appeared to be a three-way (group x phase x time) interaction for acylated ghrelin where concentrations appeared to be greater in USERS versus NON-USERS during the OP 90-min post-prandial and during the LP fasted, and 90-min post-prandial. In USERS, ghrelin appeared to be greater 90-min post-prandial in the OP versus the FP with no other apparent differences between phases. There were no apparent differences between phases in NON-USERS. There appeared to be a three-way interaction for PYY where concentrations appeared to be greater in USERS during the FP 60-min post-prandial and during the OP 30-min post-prandial. In USERS PYY appeared to be greater 60-min post-prandial during the OP versus the LP with no other apparent differences. There were no apparent differences between phases in NON-USERS. There appeared to be no effect of group or phase on GLP-1, or appetite perceptions. These data demonstrate small effects of menstrual cycle phase and oral contraceptive use on the acylated ghrelin and total PYY response to a standardized meal, with no effects on active GLP-1 or perceived appetite, though more work with a large sample size is necessary.

Differential Diagnosis of Post Pancreatitis Diabetes Mellitus Based on Pancreatic and Gut Hormone Characteristics.

Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C.

Effects of Ghrelin on Plasminogen Activator Activity in Human Umbilical Vein Endothelial Cells

Ghrelin and its growth hormone secretagogue receptor (GHSR) have been found in the placenta, both in endothelial and trophoblast cells. Ghrelin has been shown to decrease blood pressure in several systems and improve endothelial function by stimulating VEGF production. Because locally increased Ghrelin was detected in the preeclamptic fetoplacental unit, we hypothesized its involvement in the fibrinolysis and vascular tone typically observed in preeclamptic patients. This study aimed to evaluate the synthesis of plasminogen activators (PAs), PA inhibitor-1 (PAI-1), and urokinase-type PA (uPA) receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) since the components of the PA/plasmin system are vital players in the extracellular matrix remodeling process necessary for angiogenesis. HUVECs were treated for 24 h with increasing concentrations of Ghrelin (10−11–10−7 M) or IL-1β (0.1 ng/mL). PAs, PAI-1, and uPAR mRNAs were determined by real-time PCR and PA activity was determined by casein underlay. We demonstrated an increase in uPA, tissue-type PA (tPA), and uPAR mRNA; a reduction in PAI-1 mRNA in HUVECs treated with Ghrelin; and an increase in total uPA activity. In conclusion, our results suggest a potential compensatory physiological mechanism for Ghrelin in response to the maternal endothelial dysfunction observed in the preeclamptic fetoplacental unit.

Differential effects of nutritive and non-nutritive sweet mouth rinsing on appetite in adults with obesity

BackgroundExcessive added sugar intake has been associated with obesity; however, the effect of dietary sweetness on energy intake (EI) and appetite in adults with and without obesity has not yet been determined. ObjectiveTo assess the effect of mouth rinses with and without energy and sweetness on measures of appetite, and to compare responses between subjects with body mass index (BMI) between 18.5 and 24.9 kg/m2 or ≥30 kg/m2. MethodsIn this randomized, double-blind crossover study, 39 subjects (age 23±5y; 17 male, 22 female; BMI 18.5–24.9 kg/m2: n = 21; ≥30 kg/m2: n = 18) performed modified sham-feeding (MSF) with a mouth rinse containing either sucrose, sucralose, maltodextrin, or water for 2min before expectorating the solution. Blood sampling and subjective appetite assessments occurred at baseline (−5) and 15, 30, 60, and 90min post-MSF. After, EI was assessed at a buffet meal and post-meal appetite ratings were assessed hourly for 3h. ResultsPost-MSF ghrelin increased for water vs. maltodextrin (water: p = 0.03). Post-MSF cholecystokinin increased following maltodextrin-MSF (p = 0.03) and sucralose-MSF (p = 0.005) vs. sucrose for those with BMI:18.5–24.9 kg/m2 only. There was greater post-MSF desire to eat in response to water vs. sucrose (p = 0.03) and reduced fullness with sucralose for those with BMI≥30 vs. 18.5–24.9 kg/m2 (p < 0.001). There was no difference in EI at the buffet meal by mouth rinse (p = 0.98) or by BMI (p = 0.12). However, there was greater post-meal fullness following sucralose-MSF vs. water (p = 0.03) and sucrose (p = 0.004) for those with BMI≥30 vs. 18.5–24.9 kg/m2. ConclusionSucralose rinsing led to greater cephalic phase CCK release in adults with a BMI:18.5–24.9 kg/m2 only; however, ghrelin responses to unsweetened rinses were energy-specific for all adults. As subsequent EI was unaffected, further investigation of cephalic phase appetite is warranted.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial

BackgroundTranscutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. MethodsUsing a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. ResultsThere were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LimitationsTiming of ghrelin measurements, and stimulation of only left vagus nerve. ConclusiontcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Milk protein digestion and the gut microbiome influence gastrointestinal discomfort after cow milk consumption in healthy subjects

Many healthy people suffer from milk-related gastrointestinal discomfort (GID) despite not being lactose intolerant; the mechanisms underpinning such condition are unknown.This study aimed to explore milk protein digestion and related physiological responses (primary outcome), gut microbiome and gut permeability in 19 lactose-tolerant healthy nonhabitual milk consumers [NHMCs] reporting GID after consuming cow milk compared to 20 habitual milk consumers [HMCs] without GID.NHMCs and HMCs participated in a milk-load (250 mL) test, underwent blood sample collection at 6 time points over 6 h after milk consumption and collected urine samples and GID self-reports over 24 h. We measured the concentrations of 31 milk-derived bioactive peptides (BAPs), 20 amino acids, 4 hormones, 5 endocannabinoid system mediators, glucose and the dipeptidyl peptidase-IV (DPPIV) activity in blood and indoxyl sulfate in urine samples. Subjects also participated in a gut permeability test and delivered feces sample for gut microbiome analysis.Results showed that, compared to HMCs, milk consumption in NHMCs, along with GID, elicited a slower and lower increase in circulating BAPs, lower responses of ghrelin, insulin, and anandamide, a higher glucose response and serum DPPIV activity. The gut permeability of the two groups was similar, while the habitual diet, which was lower in dairy products and higher in the dietary-fibre-to-protein ratio in NHMCs, possibly shaped the gut microbiome; NHMCs exhibited lower abundance of Bifidobacteria, higher abundance of Prevotella and lower abundance of protease-coding genes, which may have reduced protein digestion, as evidenced by lower urinary excretion of indoxyl sulfate.In conclusion, the findings showed that a less efficient digestion of milk proteins, supported by a lower proteolytic capability of the gut microbiome, may explain GID in healthy people after milk consumption.

O155 Effects of oral feeding on gastric emptying and gastrointestinal hormone secretion in males with obesity compared with those of healthy weight

Abstract Introduction Hormones released in response to nutrients in the gastrointestinal (GI) tract, act as physiological signals to regulate appetite and play a role in feeding behaviours. Altered secretion of these ‘appetite’ hormones after feeding in those with obesity (‘Obese’), compared to those with healthy weight (‘Lean’), may drive over-consumption of energy. This study assessed whether gastric emptying rate was implicated in this altered response. Methods Twenty healthy males attended the laboratory once in the morning after an overnight fast. Volume of gastric contents (GCV) and small bowel water (SBW) were assessed using MRI (Philips 3T Ingenia and dStream Anterior Coil) pre, immediately post and every 30-minutes for 4-hours after a standard meal (2.5MJ, 78g Carbohydrate, 24g Protein, 21g Fat). Concurrently, arterialised-venous blood was taken for insulin, ghrelin, GLP-1 and PYY evaluation. Gastric emptying (T50) was derived from GCV. Data are presented as the mean (SD) or standardised effect size (ηp2). Results 10 Lean [38(14)y, 24(2) kg/m2] and 10 Obese [38(13)y, 34(3)kg/m2] were studied. Fasting insulin [12.5(5.8) vs. 17.6(11.3) mIU/l], Ghrelin [3.2(2.1) vs. 2.9(0.9) ng/ml], GLP-1 [7.2(11.5) vs. 13.3(2.5) pmol/l], PYY [102.3(46.7) vs. 88.4(32.4)pg/ml], SBW [121(96) vs. 168(125)ml] and GCV [59(33) vs. 59(30)ml] did not differ between ‘Lean’ and ‘Obese’. Response of Ghrelin (ηp2=0.005), GLP-1 (ηp2=0.103), PYY (ηp2=0.050) and SBWC (ηp2=0.145) to eating, and T50 [148(51) vs. 170(49) min] did not differ between groups. However, postprandial insulin secretion was greater in obese (ηp2=0.286; P&amp;lt;0.05). Conclusion Gastric emptying and incretin hormone secretion were not altered in participants with obesity. However, postprandial hyperinsulinemia, associated with insulin resistance, was observed.

Molecular Characterization and Expression Response of Ghrelin, GLP-1 and PYY to Fasting, Dietary Lipid, and Fatty Acids in Silver Pomfret (Pampus argenteus)

Ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) are potent hormones mediating food intake according to the nutritional status in fish. However, limited information is available on these genes and their expression in response to nutrition in silver pomfret (Pampus argenteus). A comparison analysis revealed that ghrelin and GLP-1 were relatively conserved in marine fish. PYYa and PYYb shared a low identity and were clustered to different PYY branches. Ghrelin, pyya, and pyyb mRNAs were highly expressed in the brain, while glp-1 was highly expressed in the gills and liver. The ghrelin mRNA expression was relatively high an hour post-feeding and decreased after 3 to 72 h of fasting. The glp-1 mRNA expression was increased after 6 to 24 h of fasting. The pyya mRNA expression was increased after 72 h of fasting, while the pyyb expression remained stable during fasting. The diet with 14% lipid promoted the expressions of glp-1, pyya, and pyyb, but inhibited the ghrelin expression. The ghrelin expression in the intestine was increased after palmitic acid, oleic acid (OA), linoleic acid (LA), α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) incubation. OA decreased the expression of glp-1 and increased the expression of pyya. The expression of pyyb was downregulated by LA, DHA, and EPA. These results suggest the importance of ghrelin, glp-1, and pyy in coordinating food intake in response to fasting, dietary lipid concentration, and fatty acids in silver pomfret.

The Effect of Non-Nutritive Sweetened Beverages on Postprandial Glycemic and Endocrine Responses: A Systematic Review and Network Meta-Analysis.

Background: There has been an emerging concern that non-nutritive sweeteners (NNS) can increase the risk of cardiometabolic disease. Much of the attention has focused on acute metabolic and endocrine responses to NNS. To examine whether these mechanisms are operational under real-world scenarios, we conducted a systematic review and network meta-analysis of acute trials comparing the effects of non-nutritive sweetened beverages (NNS beverages) with water and sugar-sweetened beverages (SSBs) in humans. Methods: MEDLINE, EMBASE, and The Cochrane Library were searched through to January 15, 2022. We included acute, single-exposure, randomized, and non-randomized, clinical trials in humans, regardless of health status. Three patterns of intake were examined: (1) uncoupling interventions, where NNS beverages were consumed alone without added energy or nutrients; (2) coupling interventions, where NNS beverages were consumed together with added energy and nutrients as carbohydrates; and (3) delayed coupling interventions, where NNS beverages were consumed as a preload prior to added energy and nutrients as carbohydrates. The primary outcome was a 2 h incremental area under the curve (iAUC) for blood glucose concentration. Secondary outcomes included 2 h iAUC for insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), ghrelin, leptin, and glucagon concentrations. Network meta-analysis and confidence in the network meta-analysis (CINeMA) were conducted in R-studio and CINeMA, respectively. Results: Thirty-six trials involving 472 predominantly healthy participants were included. Trials examined a variety of single NNS (acesulfame potassium, aspartame, cyclamate, saccharin, stevia, and sucralose) and NNS blends (acesulfame potassium + aspartame, acesulfame potassium + sucralose, acesulfame potassium + aspartame + cyclamate, and acesulfame potassium + aspartame + sucralose), along with matched water/unsweetened controls and SSBs sweetened with various caloric sugars (glucose, sucrose, and fructose). In uncoupling interventions, NNS beverages (single or blends) had no effect on postprandial glucose, insulin, GLP-1, GIP, PYY, ghrelin, and glucagon responses similar to water controls (generally, low to moderate confidence), whereas SSBs sweetened with caloric sugars (glucose and sucrose) increased postprandial glucose, insulin, GLP-1, and GIP responses with no differences in postprandial ghrelin and glucagon responses (generally, low to moderate confidence). In coupling and delayed coupling interventions, NNS beverages had no postprandial glucose and endocrine effects similar to controls (generally, low to moderate confidence). Conclusions: The available evidence suggests that NNS beverages sweetened with single or blends of NNS have no acute metabolic and endocrine effects, similar to water. These findings provide support for NNS beverages as an alternative replacement strategy for SSBs in the acute postprandial setting.

Postprandial Glucose and Gastrointestinal Hormone Responses of Healthy Subjects to Wheat Biscuits Enriched with L-Arginine or Branched-Chain Amino Acids of Plant Origin.

The study investigates the effects of wheat biscuits supplemented with plant flours originating from legumes/seeds enriched either in L-arginine (L-arg) or branched-chain amino acids (BCAAs) on postprandial glucose response of healthy subjects. Gastrointestinal hormone and amino acid responses as well as subjective appetite sensations are also evaluated. Subjects consumed wheat-based biscuits, enriched either in L-arg (ArgB) or BCAAs (BCAAsB) or a conventional wheat biscuit (CB) or a glucose solution (GS) in an acute randomized crossover design. Responses of glucose, insulin, ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glicentin, as well as those of L-arginine, L-leucine, L-isoleucine and L-valine, were evaluated over 180 min. Consumption of ArgB and BCAAsB elicited lower glucose iAUC compared to GS (p < 0.05). A lower iAUC for insulin was observed after consumption of BCAAsB (p < 0.05 compared to CB and ArgB), while ArgB elicited higher iAUC for GLP-1 accompanied by higher glicentin response (p < 0.05 compared to CB). BCAAsB and ArgB increased postprandial amino acid concentrations and caused stronger satiety effects compared to CB. Increasing protein content of wheat biscuits with supplementation of plant flours originating from legumes/seeds decreases postprandial glycemia and provides with healthier snack alternatives which can easily be incorporated into diet.

Maternal programming by high-energy diets primes ghrelin sensitivity in the offspring of rats exposed to chronic immobilization stress

Maternal overnutrition during pregnancy leads to metabolic and immune alterations, including obesity, hyperphagia, and central and peripheral inflammation in offspring. Exposure to high-energy diets during pregnancy primes ghrelin sensitivity to overfeeding in the offspring at early stages of life. Overfeeding has also been partially related to the early stages of chronic stress. We hypothesized that maternal programming sensitizes ghrelin-induced overfeeding following a chronic stress schedule in the offspring. We used a nutritional programming model exposing female Wistar rats to a cafeteria (CAF) or control diet from prepregnancy to weaning. Male offspring were injected with ghrelin and then subjected to a chronic immobilization stress (CIS) schedule, after which food intake was determined. Hypothalamic and plasma accumulation of cytokines and cortisol were evaluated using BioPlex analysis and enzyme-linked immunosorbent assay, respectively. We found that rats exposed to the CAF diet exhibited overfeeding after fasting and peripheral ghrelin administration, which was exacerbated in rats exposed to chronic stress. Offspring exposed to the CAF diet accumulated pro-inflammatory interleukin-6 (IL-6), interferon-γ, and monocyte chemoattractant protein-1 cytokines in plasma, and IL-6 cytokine in the hypothalamus. Ghrelin-sensitive overfeeding in rats exposed to CAF diet + CIS display increased cortisol levels and decreased IL-6 accumulation in plasma. Together, our results suggest that maternal nutritional programming primes susceptibility to ghrelin response for overfeeding after a CIS schedule that mirrors plasma cortisol accumulation in male offspring.

Appetite ratings and ghrelin concentrations in young adults after administration of a balanced meal. Does sex matter?

BackgroundSex-based differences in appetite ratings have been observed previously. Ghrelin is the only known orexigenic peptide hormone. Sex differences in postprandial ghrelin responses may underlie different perceptions of hunger and satiety, but results are conflicting. We conducted a parallel study to evaluate sex differences in postprandial appetite ratings and ghrelin concentration after administration of a physiological meal among students of University of Milan.MethodsTwenty-four healthy, normal weight volunteers (12 men and 12 women) aged 18–35 years were recruited. A balanced mixed meal meeting 40% of the estimated daily energy expenditure and providing 60% of calories from carbohydrates, 25% from lipids and 15% from protein was administrated. Sex differences in appetite ratings (satiety, hunger, fullness and desire to eat) and magnitude of ghrelin suppression during postprandial period (up to 180 min) were determined.ResultsIn the fasting state, men and women did not differ in appetite ratings and ghrelin concentrations. After feeding, women tended to reach peak of satiety earlier than men, who in turn reached the nadir of hunger later than women (median: 30 min, interquartile range (IQR): 1; 120 vs. 1 min, IQR 1; 1, p = 0.007). Ghrelin suppression was greater in women (median decremental AUC − 95, IQR − 122; − 66) than in men (median decremental AUC − 47, IQR − 87; − 31, p = 0.041).ConclusionsThese findings suggest sex differences in the postprandial appetite regulation that might be important for nutritional strategy to prevent and treat obesity and eating disorders.

0846 Severe OSA in a 17yr old patient with Prader Willi Syndrome and poorly controlled Diabetes Mellitus

Abstract Introduction Prader Willi Syndrome (PWS), while rare, is the most common genetic cause of obesity. It is caused by a functional loss of paternally expressed genes from chromosomal region 15q11-13. PWS is characterized by short stature, neurodevelopmental delay, obsessive-compulsive behaviors, hypothalamic dysfunction, and hyperphagia, associated with an aberrant satiety response and elevated levels of ghrelin. Excessive daytime sleepiness (EDS) and sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and central sleep apnea, are common. Report of Cases: A 17-year-old male, with PWS, morbid obesity, autism, and diabetes mellitus (DM) type-2 was referred for evaluation of snoring and EDS (Epworth Sleepiness Score 16). He had recently been admitted with diabetic ketoacidosis associated with binge eating. He had no prior sleep testing. He denied sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy. He had a body mass index of 54 kg/m2 with short stature (1.6m). On exam, he had a Mallampati score of 4 and 1+ tonsils. A recent echocardiogram was normal. Polysomnography showed sleep latency of 10 mins, apnea-hypopnea index (AHI) of 148/hr, nadir oxygen saturation of 73%, with 45% of total sleep time &amp;lt; 90%. Hypoventilation was not present. He was prescribed auto-titrating positive airway pressure (PAP) therapy. His mother was instructed to start locking access to food again. He was treated with insulin and metformin, with a plan to start on a glucagon-like peptide-1 (GLP-1) agonist. He had been on growth hormone (GH) previously, but in the context of his other morbidities, it was not reinitiated. Conclusion It is critical to screen and monitor patients with PWS for OSA, as SDB occurs in almost 70%. While PAP therapy may improve OSA, there is often residual EDS (likely due to underlying hypothalamic dysfunction), and alerting agents may be needed. GH can be considered for short stature but is contraindicated in patients with morbid obesity, untreated severe OSA, and uncontrolled diabetes. Management of diabetes, obesity, and hyperphagia in patients with PWS is challenging. Supervision and strict limitation of food intake using physical barriers are important. While data are limited, GLP-1 agonists may provide potential benefits for weight, glycemic, and appetite control in patients with PWS. Support (If Any)

The effects of diet and chronic exercise on skeletal muscle ghrelin response

BackgroundRecent findings indicate that ghrelin, particularly the unacylated form (UnAG), acutely stimulates skeletal muscle fatty acid oxidation (FAO) and can preserve insulin signaling and insulin-stimulated glucose uptake in the presence of high concentrations of saturated fatty acids. However, we recently reported that the stimulatory effect of ghrelin on FAO and subsequent ability to protect insulin stimulated glucose uptake was lost following 6-weeks (6w) of chronic high fat feeding. In the current study we examined the effects of both short-term 5 day (5d) and chronic 6w high-fat diet (HFD) on muscle ghrelin response, and whether exercise training could prevent the development of muscle ghrelin resistance with 6w of HFD Methods and ResultsSoleus muscle strips were isolated from male rats to determine the direct effects of acylated (AG) and UnAG isoforms on FAO and glucose uptake. A 5d HFD did not alter the response of soleus muscle to AG or UnAG. Conversely, 6w of HFD was associated with a loss of ghrelin's ability to stimulate FAO and protect insulin stimulated glucose uptake. Muscle response to UnAG remained intact following the 6w HFD with chronic exercise training. Unexpectedly, muscle response to both AG and UnAG was also lost after 6w of low-fat diet (LFD) consumption. Protein content of the classic ghrelin receptor, GHS-R1a, was not affected by diet or training. Corticotropin-releasing hormone receptor-2 (CRF-2R) content, a putative receptor for ghrelin in muscle, was significantly decreased in soleus from 6w HFD-fed animals and increased following exercise training. This may explain the protection of UnAG response with training in HFD-fed rats but does not explain why ghrelin response was also lost in LFD-fed animals. ConclusionsUnAG protects muscle glucose uptake during acute lipid oversupply, likely due to its ability to stimulate FAO. This effect is lost in 6w HFD-fed animals but protected with exercise training. Unexpectedly, ghrelin response was lost in 6w LFD-fed animals. The loss of ghrelin response in muscle with a LFD cannot be explained by a change in putative ghrelin receptor content. We believe that the sedentary nature of the animals is a major factor in the development of muscle ghrelin resistance and warrants further research.

Weight loss did not modify macronutrient specific response of hormones and satiety in overweight and obese people without metabolic disease – results from a clinical trial

Sustained weight loss is highly desirable in obesity. Although the role of incretins in the regulation of body weight is well known, macronutrient specific incretin response and the effects of weight loss on this response have not been investigated before. We aimed to examine GLP-1, GIP, ghrelin, insulin, and satiety response to meals with different macronutrient composition in overweight and obese subjects before and after weight loss. 32 overweight and obese participants underwent meal tests before and after weight loss intervention. Test meals were designed to be either carbohydrate (CHO), fat (FAT), or protein (PRO) enriched to test macronutrient specific response. Macronutrient specific response of GLP-1, GIP, and ghrelin before and after weight loss were the primary outcome measures. Response of insulin and satiety were predefined secondary endpoints. There were macronutrient specific response patterns of GLP-1 (PRO>FAT=CHO), GIP (CHO=FAT>PRO), and insulin (CHO>PRO=FAT). Postprandial decline of ghrelin did not differ between the test meals. Hunger, desire to eat, and prospective food consumption were highest after CHO intake (CHO>PRO=FAT) at baseline. After weight loss, fasting and postprandial GLP-1 and insulin were reduced while concomitant ghrelin levels were increased. However, the macronutrient specific hormonal response pattern did not change after weight loss. While weight loss increased hunger and desire to eat, the macronutrient specific differences were lost after weight reduction. Higher weight loss was associated with a stronger decline of PRO induced GLP-1 response (ρ=0.45, p=0.024, n=27). Both hormones and satiety showed a macronutrient specific response in overweight/obese participants with a possibly favorable role of protein. However, weight loss may cause a partial disruption of this hormone-satiety-connection as macronutrient specific response pattern of satiety scores representing impulse control in particular but not incretins disappeared. NCT02649907. https://clinicaltrials.gov/ct2/show/NCT02649907.

Pancreatic and gut hormone responses to mixed meal test in post-chronic pancreatitis diabetes mellitus

ObjectiveMore than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls. Design and methodsSixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed. ResultsParticipants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower. ConclusionsPatients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.