Physiologically relevant lactate accumulation from exercise or peripheral injection does not alter central or peripheral appetite signaling in mice.

Lactate has been implicated in exercise-induced appetite suppression though little work has explored the mechanisms underpinning its role. Recent work suggests lactate accumulation via exercise and intracerebroventricular injection can alter central appetite regulating pathways, though a supraphysiological dose of lactate was administered centrally and there was no assessment of peripheral appetite markers. Therefore, we examined how physiologically relevant lactate accumulation via exercise or intraperitoneal injection altered central and peripheral appetite signaling pathways and whether the lactate dehydrogenase inhibitor oxamate could blunt any exercise effect. Forty 10-week-old C57BL/6 J male mice (n = 10/group) were assigned to either: 1) sedentary (SED + SAL; saline); 2) exercise (EX+SAL; saline); 3) exercise with oxamate (EX+OX; 750 mg‧kg-1 body mass); or 4) lactate (SED + LAC; 1.0 g‧kg-1 body mass). Blood, stomach, and hypothalamus samples were collected ∼2 h post-exercise/injection. Though oxamate blunted exercise-induced lactate accumulation compared to the EX+SAL condition (P = 0.044, d = 0.73), there were no differences in circulating acylated ghrelin or stomach ghrelin O-acyltransferase content between groups (P > 0.213, ηp2<0.125). There were also no differences in hypothalamic content for neuropeptide Y, proopiomelanocortin, agouti-related peptide, and alpha melanocyte-stimulating hormone (P > 0.150, ηp2<0.170). Exercise did increase phosphorylated-total signal transducer and activator of transcription 3 (pSTAT3) compared to EX+OX (p = 0.065, d = 1.23) but there were no differences in other markers of lactate signaling: phosphorylated-total adenosine monophosphate activated protein kinase, and protein kinase b (P > 0.121, ηp2<0.160). Our results suggest that lactate accumulation due to exercise or peripheral injection does not alter central or peripheral appetite signaling when measured 2 h post-exercise/injection, though pSTAT3 was blunted with oxamate.

Effects of ghrelin on food caching behaviour and body composition in black-capped chickadees (Poecile atricapillus).

Several metabolic hormones signal an organism's energy balance to the brain and modulate feeding behaviours accordingly. These metabolic signals may also regulate other behaviour related to energy balance, such as food caching or hoarding. Ghrelin is one such hormone, but it appears to exert different effects on appetite and fat levels in birds and mammals. Ghrelin treatment inhibits food intake and decreases fat stores in some bird species, but these effects may differ between acylated and unacylated (des-acyl) forms of ghrelin. The effect of ghrelin on food caching in birds has been examined in only one study, that found both leptin and unacylated ghrelin reduced food caching and mass gain in coal tits (Periparus ater). We expanded on this to test how both forms of ghrelin affect food caching and body composition in black-capped chickadees (Poecile atricapillus). We injected each bird with acylated ghrelin, unacylated ghrelin, and a saline control and then measured food caching every 20 min for two hours post-injection. We also measured body mass fat levels the day before, and after treatment using quantitative magnetic resonance (QMR). Contrary to prior work, we found no effects of either form of ghrelin on food caching, or body or fat mass. Future work is required to determine if the difference between our results and those of the prior study stems from species differences in response to ghrelin and/or in the motivation to cache food, or ghrelin effects being modulated by energy reserves.

Zinc Alpha-2 Glycoprotein, Acylated Ghrelin, and Zinc Levels in Prediabetics.

BACKGROUND/AIM: Prediabetic stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) exhibit differences in the sites of insulin resistance. Serum Zinc α-2 glycoprotein (ZAG), acylated ghrelin (AG), and zinc (Zn) levels can affect IFG, IGT, and diabetic glucose tolerance (DGT) differently. This study examined the importance of ZAG, AG, and serum Zn levels in prediabetic individuals with IFG, IGT, and DGT, compared to those with normal glucose levels. PATIENTS AND METHODS: The study was conducted at Istanbul University Cerrahpasa-Cerrahpasa Faculty of Medicine. A total of n=151 volunteers were classified according to the WHO criteria for diabetes after undergoing an oral glucose tolerance test. Plasma and serum samples were measured by Inductively Coupled Plasma Optical Emission Spectroscopy, ELISA, and immunoassay. RESULTS: Prediabetic conditions became more prominent with the decrease in ZAG levels. ZAG levels showed a negative correlation with acylated ghrelin and Homeostatic Model Assessment for assessing beta-cell function and insulin resistance. Zinc levels were significantly lower in DGT. CONCLUSION: ZAG levels have regulatory effects on insulin resistance and plasma glucose levels are mediated by zinc and acylated ghrelin.

Low- and high-load resistance training exercise to volitional fatigue generate exercise-induced appetite suppression.

Research on exercise-induced appetite suppression often does not include resistance training (RT) exercise and only compared matched volumes. PURPOSE: To compare the effects of low-load and high-load RT exercise completed to volitional fatigue on appetite-regulation. METHODS: 11 resistance-trained males (24 ± 2 y) completed 3 sessions in a crossover experimental design: 1) control (CTRL); 2) RT exercise at 30% 1-repetition maximum (RM); and 3) RT exercise at 90% 1-RM. RT sessions consisted of 3 sets of 5 exercises completed to volitional fatigue. Acylated ghrelin, active glucagon-like peptide-1 (GLP-1), active peptide tyrosine (PYY), lactate, and subjective appetite perceptions were measured pre-exercise, 0-, 60-, and 120-min post-exercise. Energy intake was recorded the day before, of, and after each session. RESULTS: Lactate was elevated following both 30% (0-, 60-, 120-min post-exercise) and 90% (0-, 60-min post-exercise; P < 0.001, d > 3.92) versus CTRL, with 30% greater than 90% (0-min post-exercise; P = 0.011, d = 1.14). Acylated ghrelin was suppressed by 30% (P < 0.007, d > 1.22) and 90% (P < 0.028, d > 0.096) post-exercise versus CTRL, and 30% suppressed concentrations versus 90% (60-min post-exercise; P = 0.032, d = 0.95). There was no effect on PYY (P > 0.171, ηp2 <0.149) though GLP-1 was greater at 60-min post-exercise in 90% (P = 0.052, d = 0.86) versus CTRL. Overall appetite was suppressed 0-min post-exercise following 30% and 90% versus CTRL (P < 0.013, d > 1.10) with no other differences (P > 0.279, d < 0.56). There were no differences in energy intake (P > 0.101, ηp2 <0.319). CONCLUSIONS: RT at low- and high-loads to volitional fatigue induced appetite suppression coinciding with changes in acylated ghrelin though limited effects on anorexigenic hormones or free-living energy intake were present.

Octanoic acid-rich enteral nutrition attenuated hypercatabolism through the acylated ghrelin-POMC pathway in endotoxemic rats.

OBJECTIVES: Metabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been an important clinical therapeutic measure in septic patients; however, simple EN has not demonstrated good performance. This study aimed to investigate the effects of different concentrations of octanoic acid (OA)-rich EN on hypercatabolism in endotoxemic rats and test whether OA-rich EN could attenuate hypercatabolism through the acylated ghrelin-proopiomelanocortin (POMC) pathway. METHODS: Rats were randomly divided into six groups: sham, lipopolysaccharide (LPS), LPS + EN and LPS + EN + OA (0.25, 0.5, and 1 g/kg, respectively) groups to investigate the effects of different concentrations of OA-rich EN on hypercatabolism in endotoxemic rats. The rats were then randomly divided into four groups: sham, LPS, LPS + OA, and LPS + OA + Go-CoA-Tat, to test whether OA-rich EN attenuated hypercatabolism through the acylated ghrelin-POMC pathway. Rats received nutrition support via a gastric tube for 3 d (100 kcal/kg daily). Insulin resistance, muscle protein synthesis and atrophy, inflammatory cytokines, ghrelin in circulation and hypothalamus, ghrelin O-acyltransferase (GOAT), and the adenosine 5'-monophosphate-activated protein kinase (AMPK)-autophagy-POMC pathway were measured. RESULTS: Compared with simple EN, OA-rich EN promoted the acylation of ghrelin in a dose-dependent manner and attenuated POMC-mediated hypercatabolism in endotoxemic rats. Inhibition of GOAT activity decreased the level of acylated ghrelin and aggravated POMC-mediated hypercatabolism conferred by OA-rich EN. CONCLUSIONS: OA-rich EN could increase the level of acylated ghrelin and attenuate hypercatabolism through the acylated ghrelin-POMC pathway compared with simple EN in endotoxemic rats.

Acylated Ghrelin Activates PI3K/mTOR Signaling Pathway by Promoting ThPOK Acetylation to Promote Milk Fat Synthesis in Bovine Mammary Epithelial Cells.

Ghrelin regulates diverse physiological activities. However, the effects of this hormone on the milk fat synthesis remain unknown. This study aimed to investigate the effect of acylated ghrelin (AG) on milk fat synthesis by modifying the expression (knockdown or overexpression) of growth hormone secretagogue receptor 1a (GHSR1a) and Th-inducing POK (ThPOK) in primary bovine mammary epithelial cells (BMECs). The results showed that AG significantly increased the triglyceride relative content from 260.83 ± 9.87 to 541.67 ± 8.38 in BMECs via GHSR1a. ThPOK functions as a key regulatory target downstream of AG, activating the PI3K and mTOR signaling pathways to promote milk fat synthesis in BMECs. Moreover, AG-regulated ThPOK by increasing the EP300 activity, which promoted ThPOK acetylation to protect it from proteasomal degradation. In conclusion, AG increases ThPOK acetylation and stabilizes ThPOK through GHSR1a, thereby activating the PI3K/mTOR signaling pathway and ultimately promoting the milk fat synthesis in BMECs.

Acylated ghrelin suppresses doxorubicin-induced testicular damage and improves sperm parameters in rats via activation of Nrf2 and mammalian target of rapamycin.

Background: Exogenous administration of acylated ghrelin (AG) afforded reproductive protective effect in several animal models but not in those treated with doxorubicin (DOX). This study evaluated the protective effect of AG against DOX-induced testicular damage and impairment in sperm parameters in rats and examined the potential mechanisms of action. Materials and Methods: Adult male rats were divided into five groups (n = 8/each) as control, control + AG (40 nmol/kg/day; subcutaneous), DOX (10 mg/kg/day 1; intraperitoneal [i.p.]), DOX + AG, and DOX + AG + brusatol (an Nrf2 inhibitor) (2 mg/kg/every 3 days; i.p.). The treatment regimen continued for 65 days. Results: AG prevented testicular damage and apoptosis; increased sperm count, motility, and viability; and reduced the number of abnormal sperms. It also increased their circulatory levels of AG, des-acylated ghrelin (DAG), and AG/DAG ratio and the testicular mRNA levels of ghrelin and growth hormone secretagogue receptor 1a Concomitantly, AG increased serum and testicular testosterone levels, reduced serum levels of the follicle-stimulating hormone and luteinizing hormone, and upregulated the testicular protein levels of the steroidogenic acute regulatory protein and 3ß-hydroxysteroid dehydrogenase in DOX-treated rats. In the testes of the control and DOX-treated rats, AG increased the phosphorylation of mammalian target of rapamycin and stimulated the levels of glutathione and superoxide dismutase, as well as the nuclear activation of Nrf2. All these effects were completely prevented by co-treatment with brusatol. Conclusion: AG replacement therapy could be a novel strategy to prevent reproductive toxicity in cancer patients.

Measurement of Ghrelin as a Marker of Appetite Dysregulation in Cats with and without Chronic Kidney Disease.

Appetite abnormalities and weight loss are important comorbidities in the treatment of chronic kidney disease (CKD) in cats. Ghrelin, a key hormone involved in the regulation of appetite and metabolism, is a potential marker of appetite dysregulation in cats with CKD. The aim of this study was to compare the plasma concentrations of acylated, desacyl, and total ghrelin in normal cats and cats with CKD. Storage methodology was investigated prior to evaluating ghrelin concentrations in normal and CKD cats to facilitate clinical sample collection. Twelve normal cats and twelve cats with CKD were enrolled. Plasma acylated and total ghrelin concentrations were measured using radioimmunoassay. Desacyl ghrelin was calculated (total ghrelin minus acylated ghrelin). Cats with CKD had significantly increased total ghrelin and calculated desacyl ghrelin concentrations in comparison to normal cats (p < 0.0001 and p = 0.0001). There was no significant difference in active ghrelin concentrations between groups. Both total ghrelin and calculated desacyl ghrelin were significantly correlated with serum creatinine concentrations (p < 0.0001, r = 0.70 and p < 0.0001, r = 0.73). Elevated plasma desacyl ghrelin concentrations in cats with CKD provides evidence for dysregulation of appetite in feline CKD.

Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization.

BACKGROUND AND AIMS: Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. METHODS AND RESULTS: In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. CONCLUSION: In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05277415.

Breaking up sitting with short frequent or long infrequent physical activity breaks does not lead to compensatory changes in appetite, appetite-regulating hormones or energy intake.

The aim of this study was to determine the appetite-related responses to breaking up prolonged sitting with physical activity bouts differing in frequency and duration among adult females. Fourteen sedentary females aged 34 ± 13 years with a body mass index of 27.1 ± 6.3 kg/m2 (mean ± SD) took part in a randomised crossover trial with three, 7.5 h conditions: (1) uninterrupted sitting (SIT), (2) sitting with short frequent 2-min moderate-intensity walking breaks every 30 min (SHORT-BREAKS), and (3) sitting with longer duration, less frequent 10-min moderate-intensity walking breaks every 170-180 min (LONG-BREAKS). The intensity and total duration of physical activity was matched between the SHORT-BREAKS and LONG-BREAKS conditions. Linear mixed models were used to compare the outcomes between conditions with significance being accepted as p ≤ 0.05. There were no significant between-condition differences in hunger, satisfaction, prospective food consumption or overall appetite area under the curve (AUC) (all p ≥ 0.801). Absolute ad libitum energy intake and relative energy intake (REI) did not differ significantly between conditions (all p ≥ 0.420). Acylated ghrelin and total peptide YY incremental and total AUC did not differ significantly between conditions (all p ≥ 0.388). Yet, there was a medium effect size for the higher acylated ghrelin incremental AUC in SHORT-BREAKS versus SIT (d = 0.61); the reverse was seen for total AUC, which was lower in SHORT-BREAKS versus SIT (d = 0.69). These findings suggest that breaking up sitting does not lead to compensatory changes in appetite, appetite hormones or energy intake regardless of physical activity bout duration and frequency among adult females.

Rice Endoplasmic Protein-Derived Peptides, Rice-Ghretropins A and B, Stimulate Ghrelin Release in MGN3-1 Cells and Increase Plasma Acylated Ghrelin and Food Intake in Mice.

In this study, we demonstrated that novel rice-derived bioactive peptides promote the secretion of ghrelin, an endogenous orexigenic hormone secreted from the stomach. The enzymatic digest of rice endosperm protein with subtilisin, a microorganism-derived enzyme, stimulated acylated ghrelin secretion in the ghrelin-releasing cell line MGN3-1 and increased food intake after oral administration in mice. By performing a comprehensive analysis based on structure-activity relationships, we selected candidate peptides from over 30,000 peptides in the rice digest. Among them, we found that QAFEPIRSV and TNPWHSPRQGSF, corresponding to the amino acid sequence of the rice endoplasmic proteins glutelin A1 or A2(52-60) and B1 or B2(31-42), respectively, stimulated acylated ghrelin release in MGN3-1 cells. We named them rice-ghretropins A and B. Pyroglutamate formation of rice-ghretropin A, [pyr1]-rice-ghretropin A, also promoted ghrelin secretion. Furthermore, oral administration of rice-ghretropins increased food intake, plasma ghrelin concentration, and small intestinal transit in mice. In addition, the subtilisin digest of the rice protein significantly increased food intake for 4 h in 9 month-old (control: 0.61 ± 0.049 g; digest: 0.83 ± 0.059 g) and 24 month-old mice (control: 0.52 ± 0.067 g; digest: 1.01 ± 0.064 g). In summary, we found that novel bioactive peptides, namely, rice-ghretropins, from the enzymatic digest of rice endosperm stimulated acylated ghrelin secretion and increased food intake. This is the first report of rice-derived exogenous bioactive peptides that increase acylated ghrelin secretion.

Beyond appetite: Acylated ghrelin as a learning, memory and fear behavior-modulating hormone.

Although often referred to as a hunger hormone, recent evidence highlights a neuroprotective function of acylated ghrelin (AG) and a substantial role in the regulation of declarative and aversive memories as well as fear behavior. As such, in this review, we i) evaluate what specific stages and forms of memory, as well as which respective brain areas are affected by acylated ghrelin, ii) illustrate the plasticity-associated signaling pathways of AG in the hippocampus, also involving memory resolution-enhancing neurogenesis, iii) elucidate how the peptide modulates neurotransmitter systems (glutamate, γ-aminobutyric acid, dopamine, serotonin), iV) clarify the role of AG in conditioned taste aversion, novelty learning and the formation of spatial, recognition, auditory fear, contextual fear and passive avoidance memories in the hippocampus and amygdala as well as V) solve the mystery behind AG, its impact on the 5-HT system, the recently established link to post-traumatic stress disorder and the either fear-suppressing or fear-potentiating effects under neutral and acutely stressed conditions or chronic stress, respectively.

Does butyrylcholinesterase mediate exercise-induced and meal-induced suppression in acylated ghrelin?

Ample evidence supports the notion that an acute bout of aerobic exercise and meal consumption reduces acylated ghrelin concentration. However, the mechanisms by which this exercise- and meal-induced suppression of acylated ghrelin occurs in humans is unknown. This study aimed to examine the concentration of butyrylcholinesterase (BChE), an enzyme responsible for hydrolysing ghrelin and other appetite-related hormones in response to a single bout of running and a standardised meal in young, healthy men. Thirty-three men (aged 23 ± 2 years, mean ± standard deviation) underwent two (exercise and meal conditions) 2-h laboratory-based experiments. In the exercise condition, all participants ran for 30 min at 70% of the maximum oxygen uptake (0930-1000) and rested until 1130. In the meal condition, participants reported to the laboratory at 0930 and rested until 1000. Subsequently, they consumed a standardised meal (1000-1015) and rested until 1130. Blood samples were collected at baseline (0930), 1000, 1030, 1100 and 1130. BChE concentration was not altered in both the exercise and meal conditions (p > 0.05). However, acylated ghrelin was suppressed after exercise (p < 0.05) and meal consumption (p < 0.05). There was no association between the change in BChE concentration and the change in acylated ghrelin before and after exercise (p = 0.571). Although des-acylated ghrelin concentration did not change during exercise (p > 0.05), it decreased after meal consumption (p < 0.05). These findings suggest that BChE may not be involved in the suppression of acylated ghrelin after exercise and meal consumption.

Relationship Between Acyl and Desacyl Ghrelin Levels with Insulin Resistance and Body Fat Mass in Type 2 Diabetes Mellitus.

Purpose: Although strong evidence suggests that ghrelin plays an important role in regulating energy balance, the effects of acylated ghrelin (AG) and deacylated ghrelin (DAG) on fat mass are largely undefined. This study aimed to investigate the differential associations of both forms of ghrelin with insulin resistance and body fat mass in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 162 patients with type 2 diabetes were recruited and classified based on BMI and visceral fat area (VFA) as VFA normal group (n = 78), normal-BMI VFA obesity group (n = 20) and high-BMI VFA obesity group (n = 64). VFA and subcutaneous fat area (SFA) were detected by bioelectrical impedance analysis. Blood samples were collected to measure fasting glucose, insulin, lipids, AG and DAG levels after clinical examination. Results: Compared with VFA normal group, DAG levels were significantly lower (421.7 ± 106.0 and 388.7 ± 96.5 pg/mL vs 524.4 ± 141.5 pg/mL, P < 0.01) in the two VFA obesity groups. No significant difference was found in AG levels within three groups. Among all subjects, BMI, VFA, SFA, fasting insulin and HOMA-IR were negatively correlated with DAG but positively with AG/DAG ratio (P < 0.01). In contrast, AG was positively correlated with HOMA-IR and fasting glucose (P < 0.01). Multiple stepwise regression analysis showed that fasting glucose was the independent factor of AG, VFA and HOMA-IR were the independent factors related to DAG. Conclusion: DAG levels have a strong negative association with excess body fat mass and insulin resistance, whereas AG levels are closely related to elevated blood glucose levels in T2DM patients.

A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls.

INTRODUCTION: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels. METHODS: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH® (100 µg/m2) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels. RESULTS: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 ± 257.1 vs. 247.6 ± 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041). CONCLUSION: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels.

Ghrelin Levels in Children With Intestinal Failure Receiving Long-Term Parenteral Nutrition.

Background: Children with intestinal failure (IF) require parenteral nutrition (PN). Transition to oral and enteral nutrition (EN) can be difficult also due to abnormal gastrointestinal motility. The gut hormone ghrelin is increased in states of negative energy balance, functioning to preserve euglycemia, and also has appetite stimulating and prokinetic properties. We aimed to evaluate and compare ghrelin levels in children with IF, and to assess the relationship with PN-dependency. Methods: In this exploratory prospective multicenter study, plasma acylated (AG) and unacylated (UAG) ghrelin levels were measured in children with short bowel syndrome (SBS) and with functional IF (pseudo-obstruction or any enteropathy) and compared with healthy control subjects. Spearman's rho (rs) was used to assess correlations of AG and UAG with PN-dependency (%PN) and parenteral glucose intake. Results: Sixty-four samples from 36 IF-patients were analyzed. Median baseline AG and UAG levels were respectively 279.2 and 101.0 pg/mL in children with SBS (n = 16), 126.4 and 84.5 pg/mL in children with functional IF (n = 20) and 82.4 and 157.3 pg/mL in healthy children (n = 39). AG levels were higher in children with SBS and functional IF than in healthy children (p = 0.002 and p = 0.023, respectively). In SBS, AG positively correlated with %PN (rs = 0.5, p = 0.005) and parenteral glucose intake (rs = 0.6, p = 0.003). These correlations were not observed in functional IF. Conclusion: Children with IF had raised AG levels which could be related to starvation of the gut. The positive correlation between AG and glucose infusion rate in SBS suggests an altered glucoregulatory function.

Decreased acylated and total ghrelin levels in bipolar disorder patients recovering from a manic episode.

BACKGROUND: To date, only few studies have investigated ghrelin levels in bipolar disorders, and all have exclusively measured acylated ghrelin, with none investigating total ghrelin (acylated and des-acylated). We aimed to investigate peripheral levels of acylated and total ghrelin in subjects experiencing a manic episode of bipolar disorder. METHODS: Peripheral levels of acylated and total ghrelin were measured in hospitalised medicated individuals recovering from a manic episode. Enzyme-linked immunosorbent assays (ELISA) were used to measure ghrelin levels in patients and compared with healthy controls. The relationship between ghrelin levels in bipolar disorder, self-reported hunger measures, demographic and clinical parameters was investigated with correlational analyses. RESULTS: Twenty-four subjects (15 males, 9 females) recovering from mania and 27 matched healthy controls (13 males, 14 females) were recruited for the study. Mean values of both acylated (187 vs.520 pg/mL) and total ghrelin (396 vs. 648 pg/mL) were significantly reduced in bipolar disorder (p = 0.001). Ghrelin levels correlated positively with markers of illness severity and negatively with prescribed mood stabilizers, second-generation antipsychotics, weight and body mass index. CONCLUSION: Peripheral measurements of acylated and total ghrelin were both reduced in bipolar disorder patients compared to healthy controls. Whilst illness severity promotes higher ghrelin levels, pharmacological treatment and weight gain exercise the opposite effect.

The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome.

CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.

Changes in Appetite-Dependent Hormones and Body Composition After 8 Weeks of High-Intensity Interval Training and Vitamin D Supplementation in Sedentary Overweight Men.

Exercise and diet are important factors for energy balance and appetite regulation. The aim of this study was to investigate the effect of 8 weeks High Intensity Interval Training (HIIT) and vitamin D3 supplementation in sedentary overweight men. Forty-eight participants were randomly assigned to one of the following four groups (n = 12): HIIT + VitD, HIIT + placebo (3 sessions per week, 10 × 1 min interval cycling at 90-100% VO2peak separated by 1 min active recovery at 15% VO2peakfor 8 weeks), Vit D and control groups. Participants received 2,000 IU/day 25 (OH) D3 or placebo. Measurements were taken pre and post training after 10 h overnight fasting. Insulin, weight, BMI and body fat percentage were significantly decreased, but PYY was significantly increased in the HIIT + Vit D and HIIT + placebo groups (p = 0.001 and p = 0.001, respectively) after 8 weeks of HIIT. Insulin (p = 0.009, p = 0.001), weight, BMI and body fat percentage (p = 0.001, p = 0.001) were significantly lower in the HIIT + Vit D and HIIT + placebo groups compared to the Vit D and control groups. However, PYY was significantly higher in the HIIT + Vit D group compared to the Vit D (p = 0.025) and control groups (p = 0.007) and also in the HIIT + placebo group compared to the Vit D (p = 0.037) and control groups (p = 0.032) after 8 weeks of HIIT. The combination of regular HIIT with vitamin D supplementation has a effect on appetite control and body composition.

Effects of a 12-Week Diet versus Diet plus Aerobic and Resistance Exercise Program on Acylated and Desacylated Ghrelin, and Ghrelin O-Acyltransferase in Adolescent Girls with Obesity.

This study investigated the effects of a 12-week diet versus diet plus aerobic and resistance exercise programme on acylated ghrelin (AG), desacylated ghrelin (DAG), and ghrelin O-acyltransferase (GOAT) concentrations in girls with obesity. We randomised 30 adolescents with obesity to a 12-week aerobic and resistance exercise group (EG) or a control group (CG). At baseline and at 4, 8, and 12 weeks, we measured their body composition, lipid profile, glucose, AG, DAG, and GOAT concentrations. In the EG, the body fat percentage decreased by 2.37% and was significantly lower than that in the CG. The DAG concentrations significantly increased by 48.3% and 27.4% in the EG and CG, respectively. At 4, 8, and 12 weeks, DAG concentrations were significantly higher in the EG than in the CG. AG concentrations were higher at week 12 than at baseline in both groups. In both groups, the GOAT concentrations increased at weeks 8 and 12; however, no between-group differences were observed in the changes in GOAT concentrations. This study showed increased DAG concentrations and non-significant changes in AG and GOAT concentrations after a 12-week aerobic and resistance exercise programme in girls with obesity. These findings suggest that an aerobic and resistance exercise programme influences appetite-regulating hormones, mainly through changes in DAG concentrations.