The Future Concept of Grehlin and Anorexia Disorders

The fasting plasma ghrelin concentrations play an important role in the pathophysiology of eating disorders. Some studies reported the relationship between plasma ghrelin levels and frequency of abnormal eating behaviors, nutritional parameters in eating disorders. Ghrelin is the only known circulating hormone that acts on peripheral and central targets to increase food intake and promote adiposity. The present review focuses on the possible clinical relevance of ghrelin in the regulation of human feeding behavior in individuals with obesity and other eating disorders such as Prader-Willi syndrome, anorexia nervosa, bulimia nervosa and binge-eating.

Ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called “cholinergic-dopaminergic reward link”.

This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the “cholinergic-dopaminergic” reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour (“wanting” or “incentive motivation”). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine.

Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. The central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the treatment of substance use disorder.

Ghrelin

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients.

Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system.

Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.

Pathophysiology of eating disorders

Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs.

A ghrelin gene variant may predict crossover rate from restricting-type anorexia nervosa to other phenotypes

Patients with anorexia nervosa restricting type (AN-R) often develop bulimic symptoms and crossover to AN-binge eating/purging type (AN-BP), or to bulimia nervosa (BN). We have reported earlier that genetic variants of an orexigenic peptide ghrelin are associated with BN. Here, the relationship between a ghrelin gene variant and the rate of change from AN-R to other phenotypes of eating disorders (EDs) was investigated.

Participants were 165 patients with ED, initially diagnosed as AN-R. The dates of their AN-R onset and changes in diagnosis to other subtypes of ED were investigated retrospectively. Ghrelin gene 3056 T–>C SNP (single nucleotide polymorphism) was genotyped. Probability and hazard ratios were analyzed using life table analysis and Cox’s proportional hazard regression model, in which the starting point was the time of AN-R onset and the outcome events were the time of (i) onset of binge eating, that is, when patients changed to binge eating AN and BN and (ii) recovery of normal weight, that is, when patients changed to BN or remission.

Patients with the TT genotype at 3056 T–>C had a higher probability and hazard ratio for recovery of normal weight. The ghrelin SNP was not related with the onset of binge eating.

The 3056 T–>C SNP of the ghrelin gene is related to the probability and the rate of recovery of normal body weight from restricting-type AN.

Ghrelin receptor gene polymorphism with bulimia nervosa

Eating disorders (EDs) have a highly heterogeneous etiology and multiple genetic factors might contribute to their pathogenesis. Ghrelin, a novel growth hormone-releasing peptide, enhances appetite and increases food intake, and human ghrelin plasma levels are inversely correlated with body mass index. In the present study examined the 171T/C polymorphism of the ghrelin receptor (growth hormone secretagogue receptor, GHSR) gene in patients diagnosed with EDs, because the subjects having ghrelin gene polymorphism (Leu72Met) was not detected in a Japanese population, previously. In addition, beta3 adrenergic receptor gene polymorphism (Try64Arg) and cholecystokinin (CCK)-A receptor (R) gene polymorphism (-81A/G, -128G/T), which are both associated with obesity, were investigated. The subjects consisted of 228 Japanese patients with EDs [96 anorexia nervosa (AN), 116 bulimia nervosa (BN) and 16 not otherwise specified (NOS)]. The age- and gender-matched control group consisted of 284 unrelated Japanese subjects. The frequency of the CC type of the GHSR gene was significantly higher in BN subjects than in control subjects (chi(2) = 4.47, p = 0.035, odds ratio = 2.05, Bonferroni correction: p = 0.070), while the frequency in AN subjects was not different from that in controls. The distribution of neither beta3 adrenergic receptor gene nor CCK-AR polymorphism differed between EDs and control subjects. Therefore, the CC type of GHSR gene polymorphism (171T/C) is a risk factor for BN, but not for AN.

Tanaka find that fasting blood samples were obtained in 40 female anorexia nervosa (AN) patients, 21 restricting type (AN-R) and 19 binge-eating/purging type (AN-BP), in 31 bulimia nervosa (BN) patients, 18 purging type (BN-P) and 13 non-purging type (BN-NP), in 15 female healthy volunteers (control) before the initiation of active treatment. The fasting plasma ghrelin concentrations in all subjects were negatively correlated with nutritional parameters such as body mass index, percent body fat and serum cholinesterase concentration. The mean plasma ghrelin level in BN-P was higher than that in both BN-NP and controls despite similar nutritional parameters. The plasma ghrelin levels in both AN-R and AN-BP did not differ from BN-P despite difference of nutritional parameters. For both AN-BP and BN-P patients with habitual binge/purge behavior, there were significant correlations among plasma ghrelin values, frequencies of binge/purge cycles and serum amylase values. In BN-NP, there were no significant correlations among plasma ghrelin values, frequencies of binge-eating episodes and serum amylase values. These results suggest that habitual binge/purge behavior may have some influence on circulating plasma ghrelin levels in both BN-P and AN-BP. Habitual binge/purge cycles with vomiting as opposed to binge-eating episodes without vomiting may have a greater influence on fasting plasma ghrelin concentration in eating disorders.

Ghrelin has a role in regulating eating behavior and energy metabolism in the central nervous system, and has been reported to play an important role in the pathophysiology of anorexia nervosa (AN). The aim of the present study was to compare fasting plasma ghrelin levels in different subtypes of untreated AN patients. The subjects included 39 female AN patients and 11 female controls. The patients were then divided into two subtypes as follows: 19 AN patients with restricting (AN-R) and 20 AN patients with binge-eating/purging (AN-BP) form of the illness. Blood samples from subjects after an overnight fast were used to analyze plasma ghrelin concentrations. Plasma ghrelin concentrations in both AN-R and AN-BP were negatively correlated with body mass index (BMI). The mean plasma ghrelin levels in both AN-R and AN-BP were significantly higher than that in controls. The mean ghrelin level in AN-BP was significantly higher than that in AN-R. However, mean BMI and serum potassium in both groups were not significantly different. These results suggest that both BMI and the presence of binge-eating/purging may have some influence on fasting plasma ghrelin levels in patients with AN.

Plasma ghrelin, Eating patterns and circulating concentrations of cortisol and thyroid hormones.

Troisi was investigate the relations between plasma ghrelin concentrations, eating patterns, and circulating concentrations of cortisol and thyroid hormones in women with anorexia nervosa, bulimia nervosa, and binge-eating disorder. The patterns of disordered eating behavior were assessed using the Eating Attitudes Test (EAT-26) and the Bulimia Test-Revised (BULIT-R). In women with eating disorders, but not in healthy control women, plasma ghrelin concentrations were negatively correlated with body mass index (BMI) and plasma concentrations of thyreotropin (TSH), free T3 and free T4, and positively correlated with plasma concentrations of cortisol. The ghrelin concentrations of women with binge-eating and purging behavior were significantly lower than those of women with anorexia nervosa, restricting type, and there was a negative relation between the frequency and severity of binge-eating and purging behavior, as measured by the BULIT-R total score, and ghrelin concentrations. In a multivariate regression model controlling for the confounding effects of body mass index (BMI) and age, higher ghrelin concentrations were correlated with lower BULIT-R total scores. The results of this study did not confirm the hypothesis advanced in previous studies that ghrelin concentrations are higher in patients with binge-eating/purging forms of eating disorders. Based on these data, we suggest that, in women with eating disorders, ghrelin concentrations best reflect nutritional status rather than specific patterns of disordered eating behavior.

Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels

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 severe emaciation with abnormal fasting hypoglycemia in AN patients may cause very high levels of GH and ghrelin, that GH levels in AN patients may relate to nutritional status. Ghrelin may be influenced by not only nutritional status but also the eating behavior of the patients.

Balance in ghrelin and leptin plasma levels

Ghrelin, a 28-amino acid octanoylated peptide, has recently been identified in rat stomach as an endogenous ligand for the GH secretagogue receptor. In addition to GH-releasing properties, exogenous ghrelin injections exert orexigenic effects in both rodents and humans. As the endogenous peptide appears directly related to feeding behavior, we assessed its plasma levels in anorexia nervosa (AN) patients before and after renutrition and in constitutionally thin subjects with body mass indexes (BMIs) equivalent to those of AN women but with no abnormal feeding behavior. The relationships between plasma ghrelin levels and other neuroendocrine and nutritional parameters, such as GH, leptin, T3, and cortisol, were also investigated.

In AN patients, morning fasting plasma ghrelin levels were doubled compared with levels in controls, constitutionally thin subjects, and AN patients after renutrition. Twenty-four-hour plasma ghrelin, GH, and cortisol levels determined every 4 h were significantly increased, whereas 24-h plasma leptin levels were decreased in AN patients compared with controls and constitutionally thin subjects. Both plasma ghrelin and leptin levels returned to control values in AN patients after renutrition.

Constitutionally thin subjects displayed intermediate 24-h plasma ghrelin and leptin levels, significantly different from controls and AN patients, whereas GH and cortisol were not modified. Ghrelin was negatively correlated with BMI, leptin, and T(3) in controls, constitutionally thin subjects, and AN patients, whereas no correlation was found between GH and ghrelin or between cortisol and ghrelin. Ghrelin and BMI or T3 were still correlated after renutrition, suggesting that ghrelin is also a good nutritional indicator. Basal and GHRH-stimulated GH release were significantly increased in AN patients only. In conclusion, ghrelin is increased in AN and constitutionally thin subjects who display very low BMI but different eating behaviors, suggesting that not only is ghrelin dependent on body fat mass, but it is also influenced by nutritional status. Even though endogenous ghrelin is not strictly correlated with basal GH secretion, it may be involved in the magnitude of GHRH-induced GH release in AN patients.

References:

  • Cardona Cano S, et al. Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy.
    CNS Drugs. 2012 Apr 1;26(4):281-96.
  • Yi CX, et al. Ghrelin in eating disorders. Mol Cell Endocrinol. 2011 Jun 20;340(1):29-34.
  • Ando T, et al. A ghrelin gene variant may predict crossover rate from restricting-type anorexia nervosa to other phenotypes of eating disorders: a retrospective survival analysis. Psychiatr Genet. 2010 Aug;20(4):153-9.
  • Miyasaka K, et al. Association of ghrelin receptor gene polymorphism with bulimia nervosa in a Japanese population. J Neural Transm. 2006 Sep;113(9):1279-85.
  • Tanaka M, et al. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders. J Psychiatr Res. 2003 Jan-Feb;37(1):17-22.
  • Tanaka M, et al. Fasting plasma ghrelin levels in subtypes of anorexia nervosa.Psychoneuroendocrinology. 2003 Oct;28(7):829-35.
  • Troisi A, et al. Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones. Neuroendocrinology. 2005;81(4):259-66.
  • Tanaka M, et al. Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels in patients with anorexia nervosa.Regul Pept. 2004 Nov 15;122(3):163-8.
  • Tolle V, et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab. 2003 Jan;88(1):109-16.
  • Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav. 2006 Aug 30;89(1):71-84. .

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We are guilty of many errors and many faults. But our worst crime is abandoning the children, neglecting the fountain of life.
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