Voluntary wheel running ameliorates select paclitaxel chemotherapy-induced sickness behaviors and associated melanocortin signaling.

While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.

Pregnancy, but not dietary octanoic acid supplementation, stimulates the ghrelin-pituitary growth hormone axis in mice.

Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4-13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P < 0.001), regardless of diet. At ZT13, serum concentrations of total ghrelin (P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats.

Objective. Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats.Methods. Thirty two male Wistar rats (200-220g) were randomly divided into: control, VitC, CIS, and CIS + VitC groups. Animals received VitC (500 mg/kg/day)/saline by gavage for 3 weeks. For 24 h cumulative and post 18-20 h fasting food intake, fasting plasma ghrelin level, and body weight were measured. Gastric histopathology was also evaluated.Results. Results showed a marked increase in fasting plasma ghrelin and food intake in stressed rats compared to controls. VitC prevented the increases in stressed rats. Histological assessment indicated a positive effect of VitC on gastric glandular cells compared to control, an effect that might partially be a reason of significant increase of plasma ghrelin levels in VitC rats. Elevated plasma ghrelin in VitC group was even higher than that one in stressed group, whereas there were no significant changes in the food intake. Assessment of the percentage of changes in body weight during 21 days showed a significant increase in stressed rats compared to controls. Vitamin C treatment prevented this increase. Stressed rats also displayed depression-like behavior as indicated by sucrose test, whereas VitC ameliorated it.Conclusions. The data of the present study indicate that VitC may overcome ghrelin-induced hyperphagia and improve the abnormal feeding and depressive behavior in CIS rats.

Suppressive effect of ghrelin on nicotine-induced clock gene expression in the mouse pancreas.

Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.

Rikkunshito attenuates induction of epithelial-mesenchymal switch via activation of Sirtuin1 in ovarian cancer cells.

Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder.

Alcohol use disorder (AUD) is a leading cause of morbidity and mortality worldwide. However, treatment options, including pharmacotherapies, are limited in number and efficacy. Accumulating evidence suggests that elements of the gut-brain axis, such as neuroendocrine pathways and gut microbiome, are involved in the pathophysiology of AUD and, therefore, may be investigated as potential therapeutic targets. One pathway that has begun to be examined in this regard is the ghrelin system. Here, we review preclinical and clinical data on the relationship between ghrelin and alcohol-related outcomes, with a special focus on the role of the ghrelin system as a treatment target for AUD. Observational studies indicate that endogenous ghrelin levels are positively associated with craving for alcohol, subjective responses to alcohol, and brain activity in response to alcohol cues. Knockout rodent models suggest that deletion of the ghrelin peptide or receptor gene leads to reduction of alcohol intake and other alcohol-related outcomes. Different research groups have found that ghrelin administration increases, while ghrelin receptor (GHS-R1a) blockade reduces alcohol intake and other alcohol-related outcomes in rodents. Ghrelin administration in heavy-drinking individuals increases alcohol craving and self-administration and modulates brain activity in response to alcohol reward anticipation. PF-5190457, a GHS-R1a blocker, has been shown to be safe and tolerable when co-administered with alcohol. Furthermore, preliminary results suggest that this compound may reduce cue-elicited craving for alcohol in heavy-drinking individuals - a finding in need of replication. Collectively, the existing literature supports further examination of the ghrelin system as a therapeutic target for AUD. More research is also needed to understand the biobehavioral and molecular mechanisms underlying ghrelin's functions and to examine different interventional approaches to target the ghrelin system for AUD treatment.

Dynamic Ghrelin and GH serum levels during combined simultaneous arginine clonidine stimulation test in children with dwarfism.

BACKGROUND: Combined simultaneous arginine clonidine stimulation (CSACS) test represents a more appropriate stimulus to detect Ghrelin, for it does not affect glucose metabolism. METHODS: Fifty prepubertal children with dwarfism were recruited and further classified into normal growth hormone (NGH) and growth hormone deficiency (GHD) group with growth hormone (GH) peak cut-off value of 10 µg/l. In both groups, GH and Ghrelin serum levels were determined after the GH provocation test at 30, 60, and 120 min and the height standard deviation score (SDS) for bone age was measured six months later. RESULTS: The participants were classified into NGH (n = 24) and GHD group (n = 26). A decrease in the circulating Ghrelin levels prior to the GH peak was observed in the NGH children, whereas both GH and Ghrelin levels demonstrated a rise in the GHD children. Ghrelin level in GHD group was higher compared with NGH group and the GH peak in GHD group is lower than NGH group. The 6 months CSACS treatment could increase the height SDS in both groups. CONCLUSION: Although analogous changes were not detected in GHD group, the inverse correlation between GH and Ghrelin in NGH indicates a negative feedback lying between GH and Ghrelin.

Growth hormone therapy in children with idiopathic short stature - the effect on appetite and appetite-regulating hormones: a pilot study.

AIM: To investigate the effect of growth hormone (GH) therapy on appetite-regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE). METHODS: Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP-1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months. RESULTS: Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (p < .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (p = .045) and fasting GLP-1 (p = .038), and an increase in fasting insulin (p = .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: r = .667, p = .05; AUC: r = .788, p = .012) and REE (fasting: r = .866, p = .005; AUC: r = .847, p = .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (r = .741, p = .022) and fat-free-mass (r = .890, p = .001) at 12 months of GH treatment. CONCLUSIONS: The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated. ABBREVIATIONS: SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat-free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range.

Exendin-4 antagonizes the metabolic action of acylated ghrelinergic signaling in the hypothalamic paraventricular nucleus.

In the current study we investigated the interaction of hypothalamic paraventricular nucleus (PVN) glucagon-like peptide-1 (GLP-1) and ghrelin signaling in the control of metabolic function. We first demonstrated that acylated ghrelin injected directly into the PVN reliably altered the respiratory exchange ratio (RER) of adult male Sprague Dawley rats. All testing was carried out during the initial 2 h of the nocturnal cycle using an indirect open circuit calorimeter. Results indicated that acylated ghrelin induced a robust increase in RER representing a shift toward enhanced carbohydrate oxidation and reduced lipid utilization. In contrast, treatment with comparable dosing of des-acyl ghrelin failed to significantly impact metabolic activity. In separate groups of rats we subsequently investigated the ability of exendin-4 (Ex-4), a GLP-1 analogue, to alter acylated ghrelin's metabolic effects. Rodents were treated with either systemic or direct PVN Ex-4 followed by acyl ghrelin microinjection. While our results showed that both systemic and PVN administration of Ex-4 significantly reduced RER, importantly, Ex-4 pretreatment itself reliably inhibited the impact of ghrelin on RER. Overall, these findings provide increasingly compelling evidence that GLP-1 and ghrelin signaling interact in the neural control of metabolic function within the PVN.

Serum ghrelin and obestatin levels in HIV-infected patients: Effect of 36 weeks of antiretroviral treatment.

INTRODUCTION: Patients with HIV+ often present lipid disturbances. The role of ghrelin and obestatin in these lipid disturbances is not clear. The effect of antiretroviral (ART) drugs on those molecules is also unknown. This study measured ghrelin and obestatin levels, as well as metabolic markers, in patients with HIV+ before and after 36 weeks of ART. MATERIAL AND METHODS: Twenty HIV-positive, ART-naïve patients who started a scheme consisting of tenofovir/emtricitabine+lopinavir/ritonavir were enrolled. Plasma samples were collected before and after 36 weeks of treatment. Serum ghrelin and obestatin levels were quantitated by ELISA; glucose, cholesterol, and triglyceride levels were measured by colorimetric and enzymatic methods, and cardiovascular risk was calculated by the atherogenic index of plasma (AIP). RESULTS: All patients completed 36 weeks of ART. Total cholesterol (p<0.001), LDL-C (p=0.019), HDL-C (p=0.003), VLDL-C (p=0.002), and triglyceride levels (p=0.021) significantly increased after treatment. AIP revealed increased cardiovascular risk at baseline, which remained high after treatment. There was a statistically significant increase in obestatin level in the unpaired and paired analyses, while ghrelin levels only showed a trend to increase. Changes in ghrelin and obestatin levels positively correlated, but no correlation was seen with any metabolic parameter. CONCLUSION: After 36 weeks of ART, patients showed an altered lipid profile, but there were no significant changes in cardiovascular risk. Ghrelin and obestatin levels increased after 36 weeks of ART, but the increase was only significant for obestatin. Changes in ghrelin and obestatin positively correlate.

The Acute Effect of Oleic- or Linoleic Acid-Containing Meals on Appetite and Metabolic Markers; A Pilot Study in Overweight or Obese Individuals.

Despite the abundance of plant-derived fats in our diet, their effects on appetite, and metabolic markers, remain unclear. This single-blinded 3-way cross-over pilot study aimed to investigate the ability of the two most abundant dietary plant-derived fats, oleic (OA) and linoleic (LA) acids, to modulate postprandial appetite and levels of circulating appetite and metabolic regulators in overweight/obese individuals. Meals were a high-carbohydrate control, a high-OA or a high-LA meal, and provided 30% of participants' estimated energy requirements. Meals were consumed after an overnight fast, with blood samples collected over 3» h. Appetite parameters were assessed via a validated visual analogue scale questionnaire. Hormones and other circulating factors were quantified using multiplex immunoassays. Eight participants (age 45.8 ± 3.6 (years), body mass index 32.0 ± 1.3 (kg/m²)) completed the study. All meals significantly increased fullness and reduced desire to eat. The control and high-OA meals significantly decreased prospective food intake. The high-LA meal increased ghrelin levels (p < 0.05), a hormone which encourages food intake. This was coupled with a significant acute increase in resistin levels, which impairs insulin signaling. Taken together, this study indicates that in overweight/obese individuals, high-LA meals may promote excess energy intake and alter glucose handling, though a larger cohort may be required to strengthen results.

NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells.

Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K+) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K+ currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K+ currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K+ current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K+ currents, and the NO pathway may be involved in this process.

Effects of combined training on total ghrelin and tumor necrosis factor-α in obese middle-aged men

Abstract AIMS The aim of the present study was to investigate the effects of combined training (CT) on total ghrelin and tumor necrosis factor-α (TNF-α) levels in obese middle-aged individuals. METHODS Twenty two obese middle-aged men (49.32 ± 5.74 years; Body mass index: 30.88 ± 1.64 kg/m²) were randomly assigned to a combined training group (CTG, n = 12) or a control group (CG, n = 10). The CT consisted of aerobic (50-85% of VO2peak) and resistance (6-10 RM) training performed three times per week, 60 min per session for 24 weeks. The anthropometric measurements, cardiorespiratory test (VO2peak), maximal strength assessment (1RM) and plasma concentrations of total ghrelin and TNF-α were determined before (Pre) and after 24 weeks (Post) of the experimental period. RESULTS Decreases were found in body fat percentage (Δ% -19.8) and waist circumference (Δ% -2.8) for CTG at the Post moment as compared to the Pre moment. In addition, the CTG demonstrated increases for VO2peak (Δ% 13.4) and for 1-RM of bench press (Δ% 78.1), leg press (Δ% 22.3) and arm curl (Δ% 19.3) at the Post moment as compared to the Pre moment. However, total ghrelin levels remained unchanged for CTG and CG after the experimental period, while TNF-α levels increased for CG (p ≤ 0.05). CONCLUSION the CT protocol performed was not effective in repairing total ghrelin levels and was not correlated with changes in the TNF-α; however, the exercise training was able to improve body composition and functional capabilities and contained the worsening of systemic inflammation associated to obesity.

Investigation of the effectiveness of ghrelin treatment in lung tissue of rats with sepsis.

OBJECTIVE: We aimed to investigate the effects of exogenous ghrelin on cytokine and ghrelin levels, oxidant parameters, and apoptotic genes in lung tissue during sepsis. BACKGROUND: There was evidence that changes of apoptosis are linked with morbidity and mortality in sepsis. There were scarce studies on the effect of ghrelin on apoptotic genes and endogenous ghrelin levels during sepsis. METHODS: Male Wistar albino rats 200-250 g were separated into four groups; Control, LPS (5 mg/kg), Ghrelin (10 nmol/kg i.v.), and LPS+Ghrelin. Tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and ghrelin levels were determined from lung tissue using enzyme-linked immunosorbent assay (ELISA). TNF-α, IL-10, Bcl-2, and Bax gene expressions were calculated using quantitative real-time polymerase chain reaction (RT-PCR), tissue superoxide dismutase enzyme (SOD) activities and malondialdehyde (MDA) were determined spectrophotometerically. RESULTS: TNF-α levels decreased in the LPS+Ghrelin group compared with the LPS (p < 0.001). IL-10 and MDA levels were found highly significantly increased in the LPS and LPS+Ghrelin groups (p < 0.05). Tissue SOD activities were higher in the Ghrelin and LPS+Ghrelin group compared with the LPS (p < 0.05). TNF-α, and Bax expression levels were increased in the LPS compared with the other groups. IL-10 expression levels were increased in the experimental groups compared with the controls. Bcl-2 expression levels were increased in the Ghrelin and LPS+Ghrelin compared with other groups. CONCLUSION: Ghrelin treatment attenuated LPS-induced lung injury. Treatment with ghrelin had no impact on serum and tissue ghrelin levels, but it decreased the level of proinflammatory cytokines. We found that ghrelin treatment had an antioxidant effect on SOD levels. Also, ghrelin decreased the activity of proapoptotic Bax and increased antiapoptotic Bcl-2. Our findings suggest that administration of ghrelin may attenuate damage in lung tissue during sepsis (Fig. 4, Ref. 33).

Hunger and satiety responses to high-fat meals after a high-polyunsaturated fat diet: A randomized trial.

OBJECTIVE: Previous studies have shown that polyunsaturated fats (PUFAs) elicit a greater response in satiety after a single-meal challenge compared with other types of fats. The long-term effects of PUFAs on satiety, however, remain unknown. The aim of this study was to determine subjective and physiological hunger and satiety responses to high-fat (HF) meals before and after a 7-d PUFA-rich diet. METHODS: Twenty-six, healthy weight (body mass index 18-24.9 kg/m2), sedentary adults were randomly assigned to either a 7-d PUFA-rich diet (n = 8 men and n = 8 women) or a 7-d control diet (n = 5 men and n = 5 women). After a 3-d lead-in diet, participants reported for the baseline visit where anthropometrics, fasting visual analog scale (VAS) measurements, and a fasting blood sample were collected. Then, two HF meals (breakfast and lunch) were consumed. Postprandial blood draws and VAS measures were collected approximately every 30 min for 4 h after each meal, for a total of 8 h. RESULTS: From pre- to post-PUFA-rich diet, there was a decrease in fasting ghrelin (P < 0.05) and an increase in fasting peptide YY (PYY; P < 0.05); however, there were no changes in fasting insulin or leptin concentrations. The postprandial response for PYY was higher after the PUFA-rich diet visit compared to baseline (P < 0.01). However, there were no differences in the postprandial response for ghrelin, insulin, leptin, or VAS measures from pre- to post-diet in either the PUFA-rich diet or control (ns). CONCLUSION: A PUFA-rich diet consumed for 7 d favorably altered fasting and postprandial physiological markers of hunger and satiety; yet, did not alter subjective ratings of hunger or fullness.

Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance.

High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT) and ghrelin knockout (Ghrelin-/-) mice were subjected to ad lib. regular chow diet supplemented with either water (RD), 8% HFCS (HFCS), or 10% sucrose (SUC). We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC-fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions.

Milk basic protein increases ghrelin secretion and bone mineral density in rodents.

OBJECTIVES: Milk basic protein (MBP), a mixture of proteins isolated from bovine milk, is known to increase bone formation. Ghrelin, a stomach-derived peptide hormone, also has been reported to stimulate osteoblast formation. The aim of this study was to determine whether MBP-induced bone formation is mediated via ghrelin. METHODS: MBP was chronically administered to mice in their drinking water for 3 wk, and body weight, water intake, and bone mineral density were measured. Additionally, plasma bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase isoform 5b, and ghrelin concentrations were determined by enzyme-linked immunosorbent assay. To examine the direct effect of MBP on ghrelin secretion, gastric tissue culture and primary mucosal cells were stimulated by MBP. RESULTS: The in vivo study of young, growing mice showed that chronic MBP intake for 3 wk increased the plasma ghrelin concentration and bone mineral density of the hind limb tibia. In vitro studies using minced rat gastric mucosa tissues and primary murine isolated gastric mucosal cells revealed that MBP stimulated ghrelin release in a dose-dependent manner. Moreover, MBP-induced ghrelin secretion was partly inhibited by adrenergic blockers. CONCLUSIONS: These findings suggest a novel mechanism by which MBP directly acts on ghrelin secretion. Additionally, the elevated ghrelin level induced by MBP may act as a mediator for bone formation.

Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis.

BACKGROUND: Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet, but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. METHODS: To test the hypothesis we used four experimental groups: (1) untreated wild-type mice, (2) BChE KO mice with LUC delivered by adeno-associated virus (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, (3) KO mice given AAV for mouse BChE (i.v. only) and (4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from the age of 1 month. Body weight, body composition, daily caloric intake and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. RESULTS: Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV-BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV-BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. CONCLUSIONS: These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.

Healthy Subjects Differentially Respond to Dietary Capsaicin Correlating with Specific Gut Enterotypes.

CONTEXT: Previous population studies in evaluating the beneficial effects of capsaicin (CAP) have yielded inconclusive results, and the mechanisms responsible for possible benefit remain unclear. OBJECTIVE: The objective was to assess the effect of dietary CAP on metabolic and immune profiles and its potential associations with gut microbial patterns in healthy adults. DESIGN: In a 6-week controlled feeding trial, subjects were given the weight maintenance diet sequentially contained with 0, 5, 0, and 10 mg/d CAP from chili powder. SETTING AND PARTICIPANTS: The study was conducted in 12 healthy subjects enrolled in Third Military Medical University in Chongqing. MAIN OUTCOME MEASURES: At the end of each period, anthropometric and basal metabolism measures together with blood and fecal samples were collected. Plasma metabolic and inflammatory markers and gut microbial ecology of each subject were subsequently assessed. RESULT: Dietary CAP increased the Firmicutes/Bacteroidetes ratio and Faecalibacterium abundance, accompanied with increased plasma levels of glucagon-like peptide 1 and gastric inhibitory polypeptide and decreased plasma ghrelin level. Further enterotype analysis revealed that these subjects could be clustered into Bacteroides enterotype (E1) and Prevotella enterotype (E2), and the above beneficial effects were mainly obtained in E1 subjects. Moreover, E1 subjects had significantly higher fecal Faecalibacterium abundance and butyrate concentration after CAP interventions than those in E2 subjects. CONCLUSION: Our study showed that gut enterotypes may influence the beneficial effects of dietary CAP, providing new evidence for the personalized nutrition guidance of CAP intervention on health promotion linking with gut microbiota patterns.