Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents

Ghrelin is an orexigenic peptide and a growth hormone (GH) secretagogue. Secretory dynamics of ghrelin have not been characterized in adolescents with anorexia nervosa (AN). We hypothesized that, compared with healthy adolescents, girls with AN would have increased ghrelin concentrations measured over 12 h of nocturnal sampling from increased basal and pulsatile secretion, and endogenous ghrelin would independently predict GH and cortisol. We examined ghrelin concentration and secretory dynamics in 22 girls with AN and 18 healthy adolescents 12-18 yr old. Associations between ghrelin, various hormones, and measures of insulin resistance were examined. On Cluster analysis, girls with AN had higher ghrelin concentrations than controls, including total area under the curve (AUC) (P = 0.002), nadir (P = 0.0006), and valley levels (P = 0.002). On deconvolution analysis, secretory burst amplitude (P = 0.03) and burst mass (P = 0.04) were higher in AN, resulting in higher pulsatile (P = 0.05) and total ghrelin secretion (P = 0.03). Fasting ghrelin independently predicted GH burst frequency (r = 0.44, P = 0.005). The nutritional markers body mass index and body fat predicted postglucose and valley ghrelin but not fasting levels. Ghrelin parameters were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and IGF-I. HOMA-IR was the most significant predictor of most ghrelin parameters. Valley ghrelin independently predicted cortisol burst frequency (52% of variability), and ghrelin parameters independently predicted total triiodothyronine and LH levels. Higher ghrelin concentrations in adolescents with AN are a consequence of increased secretory burst mass and amplitude. The most important predictor of ghrelin concentration is insulin resistance, and ghrelin in turn predicts GH and cortisol burst frequency.     

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.     

Ghrelin promotes slow-wave sleep in humans

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast, cortisol showed an inverse pattern of response. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.     

Central leptin differentially modulates ultradian secretory patterns of insulin, leptin and ghrelin independent of effects on food intake and body weight

We tested the hypothesis that leptin acts centrally to differentially modulate the ultradian communication of leptin, insulin and ghrelin with the hypothalamus. The ultradian fluctuation of these hormones in plasma after central leptin gene therapy was analyzed. Increased leptin transgene expression in the hypothalamus significantly decreased energy intake and body weight concomitant with severe hypoleptinemia and hypoinsulinemia resulting from drastically suppressed peak heights with unchanged frequency discharge of these hormones. Ghrelin secretion was, however, increased solely due to increased pulse amplitude. In pair-fed control rats leptin and ghrelin secretion was unchanged. In conclusion, independent of restraint on caloric intake and weight, leptin acting centrally modulates only the pulse amplitude of ultradian rhythmicity of the three afferent signals involved in the hypothalamic integration of energy balance. Since rhythmic discharge patterns dictate target response of hormones, these findings reveal a novel hypothalamic action of leptin in the pathophysiology of the obesity-dependent metabolic syndrome.     

Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women

Ghrelin stimulates growth hormone (GH) secretion, but it is unknown whether there is a feedback of GH on ghrelin secretion. In this study, we characterized the relatedness of GH and ghrelin in a model of acute caloric deprivation in 10 healthy women (age 26.7 +/- 1.6 yr) during a 4-day fast in the early follicular phase. GH, ghrelin, and cortisol were assessed every hour over 24 h during an isocaloric diet and after a 4-day complete fast. Sampling during a normal diet at baseline demonstrated that ghrelin decreased 17.9% within 1 h after meals (P < 0.0001), but there was no meal effect on GH. BMI (22.3 +/- 0.4 vs. 21.5 +/- 0.4 kg/m2, P < 0.0001) and IGF-I (312 +/- 28 vs.124 +/- 22 ng/ml, P < 0.0001) decreased during fasting. Mean 24-h GH increased (2.6 +/- 0.5 vs. 5.6 +/- 0.5 ng/ml, P < 0.001), but ghrelin decreased (441.3 +/- 59.7 vs. 359.8 +/- 54.2 pg/ml, P = 0.012). The peak ghrelin level decreased from 483.5 to 375.6 pg/ml (P < 0.0001), and the time of the peak ghrelin changed from 0415 to 1715. In contrast, the diurnal pattern of GH was maintained, with increases in the nadir (1.1 to 3.4 ng/ml) and peak GH concentrations (4.1 to 7.9 ng/ml) from the fed to fasted state (P < 0.0001). The change in morning GH concentrations was inversely related to the change in ghrelin (r = -0.79, P = 0.012). During complete short-term caloric deprivation in healthy women, ghrelin decreases, even as GH rises, and these processes appear to be reciprocal, suggesting that GH exhibits feedback inhibition on ghrelin. Our data provide new evidence of the physiological relationship of GH and ghrelin in response to changes in protein-energy metabolism.     

Characterization of leptin pulse dynamics and relationship to fat mass,growth hormone,cortisol, and insulin

To investigate the regulation of leptin secretion and pulsatility by fat mass, we performed overnight leptin sampling every 20 min for 12 h and compared leptin dynamics with total body and regional fat measurements in 20 healthy male subjects. Simultaneous growth hormone (GH), cortisol, and insulin levels were assessed to determine relatedness and synchronicity during overnight fasting. Deconvolution analyses were performed to determine simultaneous hormonal dynamics, synchronicity, and interrelatedness using cross-correlation and cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 4.7 +/- 0.4 leptin pulses/12 h. Leptin secretion correlated highly with total body fat (r = 0.78, P < 0.001) and regional fat depots. In contrast, leptin pulsatility did not correlate with total fat (r = 0.07, P = 0.785) or other measures of fat. There was synchronicity between GH and leptin (lag -39 minutes), cortisol and leptin (lag -211 min), and leptin and insulin, with leptin following insulin by 275 min. The mean random X-ApEn was significant between leptin and GH (0.854 +/- 0.030), cortisol (0.891 +/- 0.023), and insulin (0.868 +/- 0.034), demonstrating a high degree of regularity and pattern frequency. These data demonstrate differential regulation of leptin secretion and pulsatility in adipocytes and suggest that the leptin pulse generator is extrinsic to fat, whereas fat mass acts as an amplifier to modulate secretion and amplitude for a given pulsatility. We demonstrate synchronicity between leptin and GH, cortisol, and insulin. The directionality of the cross correlation suggests a temporal construct in which changes in leptin follow those of insulin but precede those of GH and cortisol during overnight fasting.     

Leptin downregulates ghrelin levels in streptozotocin-induced diabetic mice

Ghrelin, an orexigenic peptide produced in the stomach, is increased in streptozotocin (STZ)-induced diabetic (DM) mice. This study clarifies the regulation of ghrelin levels by leptin in STZ-DM mice. STZ-DM mice had higher plasma ghrelin concentrations and greater ghrelin mRNA expression than control mice. Changes in ghrelin levels were dose dependently attenuated by the subcutaneous injection of leptin (0-27 nmol x kg(-1) x day(-1) over 7 days). Leptin treatment also partially reversed the hyperphagia and hyperglycemia observed in STZ-DM mice, but not the hypoinsulinemia, and there was a decrease in plasma ghrelin concentrations and ghrelin mRNA levels compared with STZ-LEP pair-fed mice. These results indicate that leptin treatment partially reverses elevated plasma ghrelin levels in STZ-DM mice independent of food intake and insulin, and suggest that hypoleptinemia in STZ-DM mice upregulates ghrelin.     

Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls

Amenorrhea is common in young athletes and is associated with low fat mass. However, hormonal factors that link decreased fat mass with altered gonadotropin pulsatility and amenorrhea are unclear. Low levels of leptin (an adipokine) and increased ghrelin (an orexigenic hormone that increases as fat mass decreases) impact gonadotropin pulsatility. Studies have not examined luteinizing hormone (LH) secretory dynamics in relation to leptin or ghrelin secretory dynamics in adolescent and young adult athletes. We hypothesized that 1) young amenorrheic athletes (AA) would have lower LH and leptin and higher ghrelin secretion than eumenorrheic athletes (EA) and nonathletes and 2) higher ghrelin and lower leptin would be associated with lower LH secretion. This was a cross-sectional study. We examined ghrelin and leptin secretory patterns (over 8 h, from 11 PM to 7 AM) in relation to LH secretory patterns in AA, EA, and nonathletes aged 14-21 yr. Ghrelin and leptin were assessed every 20 min and LH every 10 min. Groups did not differ for age, bone age, or BMI. However, fat mass was lower in AA than in EA and nonathletes. AA had lower LH and higher ghrelin pulsatile secretion and AUC than nonathletes and lower leptin pulsatile secretion and AUC than EA and nonathletes. Percent body fat was associated positively with LH and leptin secretion and inversely with ghrelin. In a regression model, ghrelin and leptin secretory parameters were associated independently with LH secretory parameters. We conclude that higher ghrelin and lower leptin secretion in AA related to lower fat mass may contribute to altered LH pulsatility and amenorrhea.     

Secretory patterns of leptin and luteinizing hormone in food-restricted young female sheep

Leptin, the product of the ob gene, has been proposed as a metabolic signal that regulates the secretion of GnRH/LH. This may be critical during prepubertal development to synchronize information about energy stores and the secretion of GnRH/LH. This study aimed to assess the effect of food restriction on the episodic secretion of leptin and LH in young female sheep. Five 20-week-old prepubertal females were fed a low-level diet for 10 weeks to maintain the body weight. Control females of the same age received food ad libitum. Blood samples were collected at 10-min intervals for six hours at 20, 26, and 30 weeks of age, and plasma leptin, LH, insulin and cortisol concentrations were measured. In the control group, no changes were found in pulsatile LH secretion characteristics. Mean LH concentrations and LH amplitude were lower in the food-restricted group than in the control group at 26 and 30 weeks of age. In the control group, pulsatile leptin secretion did not change. When compared to control lambs of the same age, the food-restricted group showed lower mean plasma leptin concentrations, pulse amplitude and plasma insulin levels, after 6 weeks of restriction (week 26), although by week 30, plasma leptin concentrations and plasma insulin rose to those of the control group. Leptin pulse frequency did not change, nor did mean plasma levels of insulin in the control group at any age studied. Mean plasma concentration of cortisol did not change within or between groups. These data suggest that plasma leptin concentrations may not be associated with the onset of puberty under regular feeding and natural photoperiod in lambs. Prolonged food restriction, however, induces metabolic adaptations that allow an increase of leptin during the final period, probably related to the development of some degree of insulin resistance.     

Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice

Leptin-deficient obese mice (ob/ob) have decreased circulating growth hormone (GH) and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, whereas hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression do not differ from lean controls. Given the fact that GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined whether the absence of leptin contributes to changes in the GH axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary GH axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wild-type controls (approximately 1 ng/ml). Leptin treatment reduced food intake, body weight, and circulating insulin while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST, or GHS-R mRNA levels compared with vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, but this latter effect did not reach statistical significance. In vitro, leptin (1 ng/ml, 24 h) did not affect pituitary GH, GHRH-R, or GHS-R mRNA but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH axis function in ob/ob mice.     

Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats.

Ghrelin, an endogenous growth hormone (GH) secretagogue, is shown to increase food intake, which action is similar to that of orexin, also a hypothalamic peptide. Since orexin suppresses pulsatile LH secretion in ovariectomized (OVX) rats, the present study was undertaken to investigate whether ghrelin also suppresses LH secretion. Effects of intracerebroventricularly injected ghrelin (0.1 nmol/0.3 microl) were examined in OVX rats treated with a small dose of 17beta-estradiol (E(2)). After ghrelin injection, pulsatile LH secretions which were ongoing in these E(2)-treated OVX rats were significantly suppressed for about 1 h, whereas GH secretion increased, peaking at 30 min. The main parameter suppressed by ghrelin was the pulse frequency, not the pulse amplitude, suggesting the hypothalamus as the site of ghrelin action. This study provides evidence that ghrelin acts not only in the control of food intake but also in the control of LH secretion.     

Role of adiposity hormones in the mouse during fasting and winter-acclimatization

The influence of fasting and winter-acclimatization (cold and short-day acclimatization) on mouse plasma leptin, ghrelin, growth hormone (GH) and melatonin concentrations was determined from blood samples taken at mid-day and midnight. A 16-h fast decreased the plasma leptin but almost doubled the plasma ghrelin concentrations which contribute to energy saving, appetite stimulation and, in the case of leptin, to inhibition of reproduction. Winter-acclimatization did not affect plasma ghrelin concentrations, whereas leptin decreased to the same level as in fasting. The low leptin concentrations possibly enable an increased caloric intake for the purpose of thermogenesis. Fasting and winter-acclimatization seemed to abolish the diurnal leptin rhythm, but had no effect on that of ghrelin. Plasma melatonin concentration correlated negatively with ghrelin, suggesting a possible role for melatonin in the regulation of ghrelin concentration. SNS-activity and insulin appear to be the main regulators of leptin plasma concentration in the mouse, rather than melatonin as in some seasonal mammals. Interestingly, endogenous ghrelin did not stimulate GH secretion, which is a well-documented reaction to exogenous ghrelin injections.     

The role of circulating ghrelin in growth hormone (GH) secretion in freely moving male rats

To examine the physiological significance of plasma ghrelin in generating pulsatile growth hormone (GH) secretion in rats, plasma GH and ghrelin levels were determined in freely moving male rats. Plasma GH was pulsatilely secreted as reported previously. Plasma ghrelin levels were measured by both N-RIA recognizing the active form of ghrelin and C-RIA determining total amount of ghrelin. Mean +/- SE plasma ghrelin levels determined by N-RIA and C-RIA were 21.6 +/- 8.5 and 315.5 +/- 67.5 pM, respectively, during peak periods when plasma GH levels were greater than 100 ng / ml. During trough periods when plasma GH levels were less than 10 ng / ml, they were 16.5 +/- 4.5 and 342.1 +/- 29.8 pM, respectively. There were no significant differences in plasma ghrelin levels between two periods. Next, effect of a GH secretagogue antagonist, [D-Lys-3]-GHRP-6, on plasma GH profiles was examined. There were no significant differences in both peak GH levels and area under the curves of GH (AUCs) between [D-Lys-3]-GHRP-6-treated and control rats. These findings suggest circulating ghrelin in peripheral blood does not play a role in generating pulsatile GH secretion in freely moving male rats.     

Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly

Octreotide is a potent somatostatin analog that inhibits growth hormone (GH) release and restricts somatotrope cell growth. The long-acting octreotide formulation Sandostatin LAR is effective clinically in approximately 60% of patients with acromegaly. Tumoral GH secretion in this disorder is characterized by increases in pulse amplitude and frequency, nonpulsatile (basal) release, and irregularity. Whether sustained blockade by octreotide can restore physiological secretion patterns in this setting is unknown. To address this question, we studied seven patients with GH-secreting tumors during chronic receptor agonism. Responses were monitored by sampling blood at 10-min intervals for 24 h, followed by analyses of secretion and regularity by multiparameter deconvolution and approximate entropy (ApEn). The somatostatin agonist suppressed GH secretory-burst mass, nonpulsatile (basal) GH release, and pulsatile secretion, thereby decreasing total GH secretion by 86% (range 70-96%). ApEn decreased from 1.203 +/- 0.129 to 0.804 +/- 0.141 (P = 0.032), denoting greater regularity. None of GH pulse frequency, basal GH secretion rates, or ApEn normalized. In summary, chronic somatostatin agonism is able to repress amplitude-dependent measures of excessive GH secretion in acromegaly. Presumptive tumoral autonomy is inferred by continued elevations of event frequency, overall pattern disruption (irregularity), and nonsuppressible basal GH secretion.     

Altered secretion of growth hormone and luteinizing hormone after 84 h of sustained physical exertion superimposed on caloric and sleep restriction.

The pulsatile release of growth hormone (GH) and luteinizing hormone (LH) from the anterior pituitary gland is integral for signaling secretion of insulin-like growth factor (IGF)-I and testosterone, respectively. This study examined the hypothesis that 84 h of sustained physical exertion with caloric and sleep restriction alters the secretion of GH and LH. Ten male soldiers [22 yr (SD 3), 183 cm (SD 7), 87 kg (SD 8)] had blood drawn overnight from 1800 to 0600 every 20 min for GH, LH, and leptin and every 2 h for IGF-I (total and free), IGF binding proteins-1 and -3, testosterone (total and free), glucose, and free fatty acids during a control week and after 84 h of military operational stress. Time-series cluster and deconvolution analyses assessed the secretion parameters of GH and LH. Significant results (P < or = 0.05) were as follows: body mass (-3%), fat-free mass (-2.3%), and fat mass (-7.3%) declined after military operational stress. GH and LH secretion burst amplitude (approximately 50%) and overnight pulsatile secretion (approximately 50%), IGF binding protein-1 (+67%), and free fatty acids (+33%) increased, whereas leptin (-47%), total (-27%) and free IGF-I (-32%), total (-24%) and free testosterone (-30%), and IGF binding protein-3 (-6%) decreased. GH and LH pulse number were unaffected. Because GH and LH positively regulate IGF-I and testosterone, these data imply that the physiological strain induced a certain degree of peripheral resistance. During periods of energy deficiency, amplitude modulation of GH and LH pulses may precede alterations in pulse numbers.     

Serum leptin, insulin-like growth factor-I components and sex-hormone binding globulin. Relationship with sex, age and body composition in healthy population

Leptin plays an important role in the regulation of food intake and thermogenesis, regulates long term energy balance and reproductive function and its concentrations are closely linked to body mass index. Leptin secretion is influenced by many factors and the age-related changes in different hormones might modify circulating leptin concentrations. Sex dimorphism in leptin concentrations has been clearly shown in previous studies and its concentrations were lower in men than in women in all decades of life. Insulin growth factor-I (IGF-I) is a peptide growth factor that is present in all types of physiologic fluids and is also produced by connective tissue cell types and its autocrine/paracrine secretion is nearly always present within tissues. There is a physiological decline of the growth hormone (GH)/IGF-I axis with ageing and in addition, insulin, thyroid hormones and the supply of dietary energy may directly regulate the circulating levels of the IGFs and growth hormone binding protein (GHBP). Furthermore, there is no doubt that GH participates in the regulation of body composition, and with advanced age there is a decrease in muscle and an increase in adiposity associated with a decline in GH and total IGF-I. The biological activities of the IGF ligands are modulated by the family of high affinity GHBP. Sex hormone binding globulin (SHBG) concentrations are thought to be regulated primarily through opposing actions of sex steroids on hepatic SHBG production, with oestrogen stimulating and androgen inhibiting SHBG production, and thyroid hormones are also a potent stimulator of SHBG production concentrations. Some studies support an independent IGFBP3 contribution to SHBG variability and these findings are compatible with the hypothesis that some of the anabolic effects ascribed to the GH/IGF axis may be caused by SHBG-mediated changes in testosterone activity or SHBG/total testosterone index.     

Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels in patients with anorexia nervosa

Circulating ghrelin and growth hormone (GH) are up-regulated in anorexia nervosa (AN) as a consequence of prolonged starvation. The current study examines the effect of nutritional rehabilitation with improvement of eating behavior on ghrelin and GH levels in AN patients during the course of inpatient treatment. The subjects included 34 female AN patients and 9 age-matched female controls. Fasting blood samples were collected before, during and after treatment. For data analysis, AN subjects were divided into three subtypes. The first group included seven patients with emergent hospitalization (E-AN), who were accompanied by severe emaciation due to their inability for food intake for more than a month. The other two groups included 14 AN with restricting (AN-R) and 13 AN with binge-eating/purging (AN-BP) patients. There were significant correlations between ghrelin, GH and body mass index (BMI) before treatment in all subjects. However, ghrelin levels were not significantly correlated with BMI and GH although there was a relationship between GH and BMI after treatment. Before treatment, E-AN patients had the highest levels of ghrelin and GH with the lowest glucose levels and liver dysfunction. The AN-BP group had a higher level of ghrelin than the AN-R group. During treatment, comparing with the controls group only the AN-R group showed higher level of ghrelin. Contrarily, the ghrelin levels in the E-AN group, who showed improved glucose levels, and the AN-BP group, who stopped vomiting behavior due to our treatment, decreased ghrelin levels. After treatment, only the AN-BP group showed a higher ghrelin level as compared to the controls. Although GH levels of the three AN groups decreased gradually according to our treatment progress, it still showed the higher value than the control group at the end of the treatment because every AN patients could not reach to more than 80% of their ideal body weight at discharge. These findings suggest that (1) severe emaciation with abnormal fasting hypoglycemia in AN patients may cause very high levels of GH and ghrelin, (2) that GH levels in AN patients may relate to nutritional status and (3) that ghrelin may be influenced by not only nutritional status but also the eating behavior of the patients.     

Plasma ghrelin levels in patients with end-stage renal disease

Ghrelin is an acylated peptide stimulating secretion of the growth hormone (GH). It was originally isolated from the rat stomach as an endogenous ligand for the growth hormone secretagogue receptor. Although being predominantly produced by endocrine cells of the gastric fundus, its secretion has been found in various tissues including the kidney. To study the influence of renal failure on plasma ghrelin levels we examined 16 patients with end-stage renal disease (ESRD) receiving hemodialysis (8 men and 8 women) and 19 controls (10 men and 9 women). Both groups were comparable in age and BMI. In all subjects we assessed plasma levels of ghrelin, leptin, soluble leptin receptor, insulin, IGF-I, IGFBP-1, IGFBP-3 and IGFBP-6. Ghrelin levels were significantly higher in the group of dialyzed patients (4.49+/-0.74 vs. 1.79+/-0.15 ng/ml; p<0.001). These patients had significantly higher levels of GH, IGFBP-1, IGFBP-6, leptin and percentage of body fat (p<0.05). In the group of patients with ESRD plasma ghrelin levels positively correlated with IGFBP-1 (p<0.01). In the control group, ghrelin positively correlated with GH concentrations (p<0.01) and negatively correlated with the levels of insulin and creatinine (p<0.05). In conclusion, patients with ESRD have higher ghrelin concentrations, which might be caused by a decreased excretion/metabolism of ghrelin in the kidney during renal failure.     

Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

Ghrelin is a native ligand for the growth hormone secretagogue (GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments.     

A chronic high fat diet alters the homologous and heterologous control of appetite regulating peptide receptor expression

Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS-R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents.