The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa.
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SUBMITTER: Tezenas du Montcel C
PROVIDER: S-EPMC10587521 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa.
Tezenas du Montcel Chloé C Duriez Philibert P Cao Jingxian J Lebrun Nicolas N Ramoz Nicolas N Viltart Odile O Gorwood Philip P Tolle Virginie V
iScience 20230922 11
LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed high ...[more]
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Project description:IntroductionDisruptions in homeostatic and hedonic food motivation are proposed to underlie anorexia nervosa (AN) and atypical AN, restrictive eating disorders which commonly onset in puberty. Ghrelin, a neuroprotective hormone that drives hedonic eating is increased in AN and is expressed in the hippocampus. White matter (WM) undergoes significant change during puberty in regions involved in food motivation, particularly WM tracts connected with the hippocampus. The association between ghrelin and WM region of interest (ROI) with hippocampal connections in restrictive eating disorders, particularly in adolescence during key neurodevelopmental growth, is unknown.MethodsWe evaluated fasting plasma ghrelin and WM microstructure (measured by free-water corrected fractional anisotropy (FA-t)) in WM ROIs with hippocampal connections - the fornix and the hippocampal portion of the cingulum - in 56 adolescent females (age range: 11.9 - 22.1 y; mean: 19.0 y) with low-weight eating disorders including AN and atypical AN (N = 36) and healthy controls (N = 20).ResultsFA-t in the fornix or hippocampal portion of the fornix did not differ between groups. Ghrelin was higher in AN/atypical AN vs. HC and was positively correlated with puberty stage in the AN/atypical AN group, but not the HC group. The correlation between ghrelin and FA-t in the fornix was significantly different in females with AN/atypical AN compared to controls. In AN/atypical AN, pubertal stage moderated the relation between fasting plasma ghrelin and FA-t in the fornix: higher fasting ghrelin was associated with lower FA-t in the fornix in late-post-puberty, but was not associated with FA-t in the early to mid stages of puberty.ConclusionsIn post-pubertal females with low-weight AN/atypical AN, higher levels of ghrelin are associated with lower FA-t in the fornix. This relationship is not evident in the early to mid stages of puberty in AN/atypical AN or in HC, and may reflect a lack of possible neuroprotective effects of ghrelin in late-post puberty only. Understanding the effects of ghrelin on WM microstructure longitudinally and following recovery from AN/Atypical AN and how this differs across pubertal stages will be an important next step. These findings could ultimately inform treatment staging and aid in diagnosis and detection of AN/atypical AN.
| S-EPMC8629489 | biostudies-literature
Project description:ImportanceIndividuals with anorexia nervosa maintain extremely low body weights despite elevations in the circulating orexigenic hormone ghrelin. Whether circulating levels of endogenous ghrelin are associated with weight gain in anorexia nervosa is unknown.ObjectiveTo examine the association between baseline ghrelin and future weight change in individuals with anorexia nervosa.Design, setting, and participantsThis prospective cohort study was conducted between April 1, 2014, and March 31, 2020, in the US. Girls and women aged 10 to 22 years were recruited from the greater Boston area from community and area treatment centers, enrolled, and followed up for 18 months. Statistical analyses were performed between January and August 2022.ExposuresPresence or absence of anorexia nervosa and elevations in endogenous ghrelin.Main outcomes and measuresChanges in age- and sex-standardized body mass index percentiles from baseline to 9- and 18-month follow-up were the main outcomes of interest.ResultsA total of 68 girls and young women (11 [16%] Asian, 4 [6%] Hispanic or Latina, 51 [75%] White [non-Hispanic or Latina], and 2 [3%] other race or ethnicity), including 35 with anorexia nervosa and 33 healthy controls of similar Tanner stage, were included in this study. Anorexia nervosa and healthy control groups were not statistically different by race and ethnicity, Tanner stage, number completing follow-up visits, and the duration between baseline and follow-up visits. At baseline, individuals with anorexia nervosa were slightly older (median [IQR], 20.1 [18.5-21.0] vs 18.7 [14.7-19.4] years; P = .005), had lower body mass index percentiles (median [IQR], 2.4 [0.3-4.7] vs 52.9 [40.4-68.3]; P < .001), and had elevated circulating ghrelin area under the curve composite index (median [IQR], 1389.4 [1082.5-1646.4] vs 958.5 [743.0-1234.5] pg/mL; P = .003) compared with healthy individuals. In linear mixed-effects regression analyses, baseline ghrelin was associated with prospective weight gain after adjusting for diagnosis, age, race, and duration of follow-up (odds ratio, 2.35; 95% CI, 1.43-3.73; P = .004).Conclusions and relevanceIn this cohort study, endogenous ghrelin was associated with longitudinal weight gain in individuals with anorexia nervosa. Further studies are warranted to confirm this result and examine its potential clinical utility in treatment development.
| S-EPMC10313149 | biostudies-literature
Project description:The growing interest concerning the role of metabolic sensors in various eating disorders requires the implementation of a strict methodology to collect, store and process blood samples in clinical studies. In particular, measurement of isoforms of the appetite-stimulating hormone, ghrelin, has been challenging in clinical settings. Indeed the acyl ghrelin (AG) isoform is rapidly degraded into desacyl ghrelin (DAG) by blood esterases, thus optimal conditions for the conservation of AG and accurate determination of AG/DAG ratio should be used. Here, we compared different protease inhibitors (Aprotinin, PHMB, AEBSF) during blood collection, increasing delays (0-180 min) before centrifugation, plasma supplementation with various HCl concentrations, storage durations of frozen plasma (8 and 447 days) and immunoenzyme-assay procedures (one-step versus sequential) in healthy subjects. Optimal conditions were obtained by collecting blood with aprotinin and supplementation of plasma with 0.1 N HCl with subsequent freezing for at least 8 days and using one-step assay. Under such conditions, different patterns of secretion of ghrelin isoforms were characterized in patients with restrictive-type anorexia nervosa (AN-R) before and after nutritional recovery. We illustrate the pulsatile variations of ghrelin isoforms according to the time around a meal and hunger rates in 3 patients with AN-R. This study offers a comprehensive comparison of various conditions using selective and specific immunoassays for both ghrelin isoforms in order to optimize assay sensitivity and consistency among procedures. These assay conditions could therefore be widely used to elucidate precisely the role of ghrelin isoforms on eating behavior in physiological and pathological situations.
| S-EPMC9227986 | biostudies-literature
Project description:Anorexia nervosa (AN) is a mental health disorder that has serious physical, emotional and social consequences. Whilst cognitive behavioural therapy for AN (CBT-AN) has demonstrated efficacy, there remains a global need to improve AN treatment. Compulsive exercise activity therapy (LEAP) is an active therapy consisting of the addition to CBT-AN of eight specific sessions that focus on exercise and motivation for behavioural change. This paper presents a secondary analysis of 74 female participants in a randomised control trial of LEAP plus CBT-AN versus CBT-AN alone. The main aim of this study was to explore putative predictors and to estimate the magnitude of changes due to LEAP for specific outcome measures. Participants (LEAP: n = 36; CBT-AN: n = 38) were assessed at three successive surveys: baseline, end of therapy, and 6 months post-therapy. The overall effect sizes for changes between baseline to end of therapy and baseline to 6-month follow-up assessment showed large effect sizes (Cohen's d > = 0.80) for mental-health-related quality of life (MHRQoL), weight concern, dietary restraint, eating concern, AN stage change, and psychological distress (all p < 0.05). The results also indicated that several pre-treatment characteristics, including body mass index (BMI), level of eating disorder (ED) symptoms, and MHRQoL are important for identifying whether a treatment is likely to be effective. Future treatment programs should aim to optimise early improvements in BMI, ED symptoms, and MHRQoL.
| S-EPMC10451721 | biostudies-literature
Project description:Anorexia nervosa (AN) is a psychiatric disorder with an estimated heritability of around 70%. Although the largest genome-wide association study meta-analysis on AN identified independent loci-conferring risk to the disorder, the molecular mechanisms underlying the genetic basis of AN remains to be elucidated. To explore AN, we ran a transcriptome profiling in peripheral blood mononuclear cells of 15 AN subjects and 15 healthy controls. We validated our mean results in a mouse model of chronic food restriction mimicking several aspects of AN. Through this exploratory study we identified 673 significantly differentially expressed genes in AN. Among these genes, we identified the Vanin-1 (Vnn1) gene that appears to play a major role in the regulation of multiple metabolic pathways. We confirmed an underexpression of Vnn1, especially in the liver, in a mouse model of chronic food restriction. These results indicate that quantitative food restriction affects Vnn1 expression, suggesting that this gene may contribute to the anorexic phenotype in the chronic food restriction mouse model as well as in patients affected by AN. We believe that this report highlights promising candidate genes and gene pathways for AN and reveals Vnn1 as a biomarker that may be used as molecular targets to predict and/or to understand AN.
2023-10-31 | GSE245978 | GEO
Project description:To assess the effects of relamorelin-an agonist of the appetite-stimulating hormone ghrelin, which has effects on gastric emptying-on (1) weight gain and (2) gastric emptying in women with anorexia nervosa. In a randomized, double-blind, placebo-controlled design, the effects of the ghrelin agonist relamorelin were studied in 22 outpatient women with anorexia nervosa, diagnosed using DSM-5 criteria. The study was conducted at the Massachusetts General Hospital Clinical Research Center between March 11, 2013, and February 26, 2015. Ten participants were randomly assigned to relamorelin 100 μg subcutaneously daily (mean ± SEM age: 28.9 ± 2.4 y), and 12 were randomly assigned to placebo (28.9 ± 1.9 y). We measured changes in weight and gastric emptying time using a gastric emptying breath test (GEBT) for relamorelin versus placebo after 4 weeks of treatment. At baseline, subjects did not differ in weight, plasma ghrelin levels, or gastric emptying time. Three subjects randomized to relamorelin stopped use of the study medication due to reported feelings of increased hunger. After 4 weeks, there was a trend toward an increase in weight in participants randomized to relamorelin (mean ± SEM change: 0.86 ± 0.40 kg) compared to placebo (0.04 ± 0.28 kg; P = .07), and gastric emptying time was significantly shorter in patients taking relamorelin (median [interquartile range]: 58.0 [51.0, 78.0] minutes) compared to placebo (85.0 [75.8,100.5] minutes; P = .03). Treatment with a ghrelin agonist in women with anorexia nervosa significantly decreases gastric emptying time, leads to a trend in weight gain after only 4 weeks, and is well-tolerated. Further study is necessary to determine the long-term safety and efficacy of a ghrelin agonist in the treatment of anorexia nervosa. ClinicalTrials.gov identifier: NCT01642550.
| S-EPMC6908430 | biostudies-literature
Project description:Functional imaging data in adult patients with anorexia nervosa (AN) support a dysfunctional signal in the ventral striatum as neural signature of AN. In the present study, development of this signal was investigated with the prediction that a characteristic pattern of ventral-striatal signalling will be shown in response to cues associated with food restriction that reflects the evolvement of starvation dependence over time. The signal was assessed in adolescent patients with AN, whose duration of illness was about five times shorter relative to the adult sample. During functional magnetic resonance imaging subjects were required to estimate weights of body images (underweight, normal weight, overweight) and to process each stimulus in a self-referring way. Relative to age-matched, young healthy controls, underweight stimuli were already associated with greater activity of the ventral striatum, and processing of normal-weight stimuli elicited already reduced signalling. Subjective preferences showed exactly the same pattern of results. Relative to adult AN, the present data reveal a developing dysfunctional signal that, if untreated, will essentially contribute to the maintenance of AN. We discuss putative mechanisms that may play a crucial role in the development of AN, and also deduce new hypotheses about the involvement of the midbrain dopamine system, of which illness-related alterations may contribute to the development of AN.
| S-EPMC3818005 | biostudies-literature
Project description:As part of the Genetic Consortium for Anorexia Nervosa (GCAN) and Wellcome Trust Case
Control Consortium 3 (WTCCC3), we have amassed the largest anorexia nervosa (AN)
sample in the world (~4,000). Following the WTCCC3 GWAS, we secured funding from the
Klarman Family Foundation to extend the genetic analyses to variants on the exome chip
(CoreExome array). This pre-lim relates to carrying out genotyping on the CoreExome array
on up to a maximum of 580 new samples.
| EGAS00001000913 | EGA
Project description:Anorexia nervosa (AN) is a complex debilitating disease characterized by intense fear of weight gain and excessive exercise. It is the deadliest of any psychiatric disorder with a high rate of recidivism, yet its pathophysiology is unclear. The Activity-Based Anorexia (ABA) paradigm is a widely accepted mouse model of AN that recapitulates hypophagia and hyperactivity despite reduced body weight, however, not the chronicity. Here, we modified the prototypical ABA paradigm to increase the time to lose 25% of baseline body weight from less than 7 days to more than 2 weeks. We used this paradigm to identify persistently altered genes after weight restoration that represent a metabolic memory of under-nutrition and may contribute to AN relapse. We focused on adipose tissue as it was identified as a major location of metabolic memory of over-nutririon. We identified 300 persistently dysregulated genes, including Calm2 and Vps13d, which could be potential global regulators of metabolic memory in both chronic over- and under-nutrition. However, despite being on the opposite spectrum of weight perturbations, the majority of metabolic memory genes of under- and over-nutrition do not overlap, suggestive of the different mechanisms involved in these extreme nutritional statuses.
2023-08-23 | GSE229316 | GEO
Project description:ImportanceObservational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown.ObjectivesTo investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank.Design, setting, and participantsThis genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47 082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023.ExposuresGenetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration.Main outcomes and measuresChronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank.ResultsThe anorexia nervosa genome-wide association study included 16 992 cases (87.7%-97.4% female) and 55 525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (β = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (β = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (β = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47 082 participants with a mean (SD) age of 60.4 (17.0) years and 25 318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits.Conclusions and relevanceThe results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.
| S-EPMC10767597 | biostudies-literature