Leptin, but not ghrelin, is associated with food addiction scores in a population-based subject sample.

Background: Ghrelin and leptin are both peptide hormones and act as opposing players in the regulation of hunger, satiety and energy expenditure. Leptin reduces appetite and feelings of hunger and is secreted mainly by adipocytes, while ghrelin increases appetite and food intake and reduces metabolic rate. Both hormones have been implicated in addictive disorders. Ghrelin was shown to have pro-addictive effects while leptin's role in addiction yields more conflicting results. Their involvement in the regulation of both food intake and addictive behaviors make them interesting candidates when investigating the regulation of food addiction. However, only few human studies have been performed and large-scale studies are lacking to date. We aimed to investigate the association between total ghrelin and leptin serum levels with scores in the Yale Food Addiction Scale (YFAS). Methods: Subjects were recruited in the LIFE Adult cohort. 909 subjects were included in the analysis and we performed univariate multiple linear regression models, adjusted for age, sex (in total group analyses only), alcohol consumption, smoking status, BMI scores, cortisol concentrations, Center for Epidemiological Studies Depression Scale (CES-D) and the 7-item Generalized Anxiety Disorder Scale (GAD-7) sum scores. The dependent variable was the YFAS score. Results: In men, leptin serum levels showed a significant positive association (standardized ß = 0.146; p = 0.012) with the YFAS score. This finding was confirmed in an extreme-group comparison: men in the highest quartile of leptin levels had significantly higher YFAS sum scores than men in the lowest quartile (1.55 vs. 1.18; p = 0.00014). There was no association with YFAS sum score in the total group (standardized ß = -0.002; p = 0.974) or in women (standardized ß = -0.034; p = 0.674). Total serum ghrelin showed no association with YFAS sum score neither in the total group (standardized ß = -0.043; p = 0.196) nor in men (n = 530; standardized ß = -0.063; p = 0.135) or women (n = 379; standardized ß = -0.035; p = 0.494). Conclusion: Our findings are in line with previous literature and suggest that total ghrelin serum levels are not associated with food addiction scores. Leptin had been previously shown to be associated with food addiction and we confirmed this finding for men in a large, population-based approach.

Childhood sexual abuse is associated with higher total ghrelin serum levels in adulthood: results from a large, population-based study.

Ghrelin is an orexigenic peptide hormone synthesized in times of stress and hunger and alterations of the ghrelin system following acute stressors could be repeatedly shown in humans. However, little data exists on long-term effects of trauma on the ghrelin system. We aimed to investigate the influence of childhood trauma on total ghrelin serum levels in a large, population-based study. Total serum ghrelin was measured in 1666 participants of a population-based cross-sectional study ('LIFE study'). The Childhood Trauma Screener (CTS) was used for the assessment of childhood trauma in the final sample (n = 1086; mean age: 57.10 ± 16.23 years; 632 males, 454 females). Multiple linear regression analyses and generalized linear models were chosen to examine the association between childhood trauma and total serum ghrelin concentrations. Childhood sexual abuse went along with significantly higher ghrelin serum levels in the total sample (ß = 0.114, t = 3.958; p = 0.00008) and in women (ß = 0.142, t = 3.115; p = 0.002), but not in men (ß = 0.055; t = 1.388; p = 0.166). Women with severe emotional neglect in the childhood had higher ghrelin levels than those without (odds ratio = 1.204; p = 0.018). For the CTS Sum Score and other CTS sub-scale scores, no significant association with ghrelin serum levels was found. Our study is the first to show associations between childhood sexual trauma and total ghrelin levels in adults in a large, community-based sample. Our results should initiate further research of the role of ghrelin in human stress response in prospective study designs.

Association Between Self-rating Depression Scores and Total Ghrelin and Adipokine Serum Levels in a Large Population-Based Sample.

Background: Ghrelin and the adipokines leptin and adiponectin have been suggested to be involved in mood and anxiety regulation and to be altered in affective disorders. However, studies investigating the association between ghrelin, leptin and adiponectin and depressive symptomatology are scarce but might contribute to a better understanding of their involvement in mood regulation. We thus aimed investigating the association between depressive symptomatology and total ghrelin as well as leptin and adiponectin serum levels in a large population-based sample. Methods: Total serum ghrelin, adiponectin and leptin levels were determined in 1666 subjects of a population-based cross-sectional study ("LIFE"). The Center for Epidemiological Studies Depression Scale (CES-D) and the Inventory of Depressive Symptoms - Self Rating (IDS-SR) were administered. Multiple linear regression analyses were conducted to examine the association between total serum ghrelin, leptin and adiponectin and the intensity of depressive symptoms. Results: In the total sample (n = 1,092), neither ghrelin nor leptin or adiponectin serum levels showed a significant association with CES-D or IDS-SR sum scores (N = 1,092) or in depressed/non-depressed subjects. Leptin serum levels showed a significantly positive association with IDS-SR sum scores in elderly men (≥60 years; ß = 0.122, 95% CI: 0.009; 0.236; p = 0.035). Conclusion: Our study suggests that peripheral levels of ghrelin and adipokines in a cross-sectional study design might not be sufficient to measure their involvement in depression, suggesting that associations are more complex and multi-layered.

Serum ghrelin is positively associated with physiological anxiety but negatively associated with pathological anxiety in humans: Data from a large community-based study.

The orexigenic hormone ghrelin is being increasingly recognized as a stress hormone being involved in anxiety regulation. In animals, ghrelin effects on, and responses to acute stress differed from those in chronic stress, an animal model for anxiety and depression. In humans, elevated ghrelin levels were reported in pathological anxiety (e.g. panic disorder). However, no reports exist on physiological anxiety in mentally healthy subjects. In addition, reports on generalized anxiety symptoms, both in mentally healthy subjects (e.g. worrying) or in adult patients, are lacking. Total serum ghrelin was determined in 1666 subjects of a population-based cross-sectional study ('LIFE'). The 7-item Generalized Anxiety Disorder Scale (GAD-7), detecting also other anxiety disorders, was administered. For multiple linear regression analyses, 1091 subjects were finally included. Serum ghrelin and GAD-7 scores were positively but not significantly associated in the total group (ß=0.00025, standardized ß = 0.039, 95%CI: -0.00006;0.0006;p = 0.144), in subjects with no more than mild anxiety, there was a significant positive association (GAD-7 ≤9: n = 1061, 97.25%, ß = 0.00032; standardized ß = 0.060; 95%CI: 0.000023;0.00062;p = 0.036). In contrast, there was a negative association in subjects with anxiety symptoms above the GAD-7 cut-off (GAD-7 ≥10: n = 30, 2.75%, ß=-0.003, standardized ß = -0.462; 95% CI:-0.006;0.0001;p = 0.045). Ghrelin levels were only numerically (p = 0.23) higher in subjects with clinically relevant anxiety symptoms (963.5 ± 399.6 pg/ml; mean±SD) than in those without (901.0 ± 416.4 pg/ml). In conclusion, the positive association between ghrelin and no more than mild anxiety is an initial indication for a role for ghrelin in the regulation of physiological anxiety in humans. This association and the opposed association in pathological anxiety resemble findings in animals showing diverging ghrelin effects in acute and chronic stress.

Genome-wide association and transcriptome analysis suggests total serum ghrelin to be linked with GFRAL.

OBJECTIVE: Ghrelin is an orexigenic peptide hormone involved in the regulation of energy homeostasis, food intake and glucose metabolism. Serum levels increase anticipating a meal and fall afterwards. Underlying genetic mechanisms of the ghrelin secretion are unknown. METHODS: Total serum ghrelin was measured in 1501 subjects selected from the population-based LIFE-ADULT-sample after an overnight fast. A genome-wide association study (GWAS) was performed. Gene-based expression association analyses (transcriptome-wide association study (TWAS)) are statistical tests associating genetically predicted expression to a certain trait and were done using MetaXcan. RESULTS: In the GWAS, three loci reached genome-wide significance: the WW-domain containing the oxidoreductase-gene (WWOX; P = 1.80E-10) on chromosome 16q23.3-24.1 (SNP: rs76823993); the contactin-associated protein-like 2 gene (CNTNAP2; P = 9.0E-9) on chromosome 7q35-q36 (SNP: rs192092592) and the ghrelin And obestatin prepropeptide gene (GHRL; P = 2.72E-8) on chromosome 3p25.3 (SNP: rs143729751). In the TWAS, the three genes where the expression was strongest associated with serum ghrelin levels was the ribosomal protein L36 (RPL36; P = 1.3E-06, FDR = 0.011, positively correlated), AP1B1 (P = 1.1E-5, FDR = 0.048, negatively correlated) and the GDNF family receptor alpha like (GFRAL), receptor of the anorexigenic growth differentiation factor-15 (GDF15), (P = 1.8E-05, FDR = 0.15, also negatively correlated). CONCLUSIONS: The three genome-wide significant genetic loci from the GWA and the genes identified in the TWA are functionally plausible and should initiate further research.

Higher fasting ghrelin serum levels in active smokers than in former and never-smokers.

OBJECTIVES: Ghrelin, an orexigenic peptide hormone, promotes drug reward and is suspected to play a role in nicotine dependence. However, there is little data on whether ghrelin levels are associated with active and/or former smoking. The relationship between ghrelin serum levels and smoking status in a population-based sample of individuals was studied. METHODS: Total ghrelin was determined after an overnight fast in 1519 subjects participating in a population-based cohort study ('LIFE-Adult'). Tobacco consumption was assessed using both the questionnaire and interview. Generalised linear models with gamma distribution and log-link function were performed to analyse the association of total serum ghrelin with smoking status and the association between serum ghrelin and the amount of tobacco consumed in active smokers. RESULTS: Ghrelin levels were positively associated with active, but not former smoking (OR = 1.095; p = .002). This association was not moderated by sex (interaction of 'active smoking' and sex: p = .346). Ghrelin levels were not associated with the amount of tobacco consumed in active smokers. CONCLUSIONS: This study provides evidence that total ghrelin serum levels are positively associated with active smoking. No association was found for former smokers. A unique feature of the study is the large sample size.

Vulnerability to bipolar disorder is linked to sleep and sleepiness.

Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.

Alcohol consumption is positively associated with fasting serum ghrelin in non-dependent adults: Results from the population-based LIFE-Adult-Study.

BACKGROUND: Animal experiments and studies in alcohol dependent patients indicate that ghrelin signaling in the brain is causally involved in the regulation of alcohol reward and intake. Increasing ghrelin levels enhances alcohol craving and intake, blocking ghrelin receptors abolishes these effects. If ghrelin is also involved in non-dependent alcohol consumption in humans, though, remains unknown. The aim was therefore to investigate the relationship between ghrelin serum levels and alcohol consumption in a large population-based sample. METHODS: Total ghrelin was determined after an overnight fast in 1666 subjects participating in a population-based cross-sectional study ('LIFE') including 10,000 adults. 1521 subjects were included in this analysis. Alcohol consumption was assessed using a food frequency questionnaire (FFQ). Multiple linear regression analyses and extreme group comparisons testing for statistical differences of alcohol consumption between the highest and lowest quartile according to ghrelin levels were performed. RESULTS: Alcohol consumption was positively associated with serum ghrelin; total sample: ß = 0.003, p = 0.002; men: ß = 0.005, p = 0.023; women: ß = 0.002, p = 0.007, adjusted for age, BMI and smoking status. Mean alcohol consumption in men/women belonging to the highest quartile of serum ghrelin levels (men: 21.5 (21.1) g/day; women: 7.5 (11.4) g/day) was considerably higher than in those belonging to the lowest quartile (men: 16.5 (19.3) g/day p < 0.002; women: 4.59 (10.7) g/day p = 0.0001). CONCLUSION: This is the first study showing that alcohol consumption is positively associated with serum ghrelin in a population-based sample. The study provides an initial indication that ghrelin is also involved in the regulation of alcohol consumption in non-dependent subjects.

Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder.

OBJECTIVES: The arousal regulation model of affective disorders attributes an important role in the pathophysiology of affective disorders to dysregulation of brain arousal regulation. According to this model, sensation avoidance and withdrawal in depression and sensation seeking and hyperactivity in mania can be explained as auto-regulatory attempts to counteract a tonically high (depression) or unstable (mania) arousal. The aim of this study was to compare brain arousal regulation between manic and depressive bipolar patients and healthy controls. We hypothesized that currently depressed patients with bipolar disorder show hyperstable arousal regulation, while currently manic patients show unstable arousal regulation. METHODS: Twenty-eight patients with bipolar disorder received a 15-min resting electroencephalogram (EEG) during a depressive episode and 19 patients received the same during a manic/hypomanic episode. Twenty-eight healthy control subjects were matched for age and sex. The Vigilance Algorithm Leipzig (VIGALL), which classifies 1-s EEG segments as one of seven EEG-vigilance substages, was used to measure brain arousal regulation. RESULTS: Manic patients showed more unstable EEG-vigilance regulation as compared to the control sample (P = .004) and to patients with a depressive episode (P ≤ .001). Depressive patients had significantly higher mean vigilance levels (P = .045) than controls. CONCLUSIONS: A clear difference was found in the regulation of brain arousal of manic patients vs depressive patients and controls. These data suggest that brain arousal might depend on the current mood state, which would support the arousal regulation model of affective disorders.

Assessment of Wakefulness and Brain Arousal Regulation in Psychiatric Research.

During the last few decades, much knowledge has been gained about sleep being a heterogeneous condition with several distinct sleep stages that represent fundamentally different physiological states. The same applies for the wake state which also comprises distinct global functional states (called vigilance stages). However, various terms and concepts have been introduced describing different aspects of wakefulness, and accordingly several methods of assessment exist, e.g. sleep laboratory assessments (Multiple Sleep Latency Test, Maintenance of Wakefulness Test), questionnaires (Epworth Sleepiness Scale, Karolinska Sleepiness Scale), behavioural tasks (Psychomotor Vigilance Test) or electroencephalography (EEG)-based assessments (Alpha Attenuation Test, Karolinska Drowsiness Test). Furthermore, several theoretical concepts about the regulation of sleep and wakefulness have been put forward, and physiological correlates have been identified. Most relevant for healthy functioning is the regulation of brain arousal and the adaption of wakefulness to the environmental and situational needs so that the optimal balance between energy conservation and responsiveness can be obtained. Since one approach to the assessment of brain arousal regulation is the classification of EEG vigilance stages, a computer-based algorithm (Vigilance Algorithm Leipzig) has been introduced, allowing classification of EEG vigilance stages in EEG recordings under resting conditions. The time course of EEG vigilance stages in EEGs of 15-20 min duration allows estimation of the individual arousal regulation (hyperstable, adaptive, or unstable vigilance pattern). The vigilance model of affective disorders and attention-deficit/hyperactivity disorder links a disturbed arousal regulation to the pathogenesis of psychiatric disorders and accordingly helps to explain and possibly also predict treatment effects of pharmacological and non-pharmacological interventions for these conditions.

Ghrelin in psychiatric disorders - A review.

Ghrelin is a 28-amino-acid peptide hormone, first described in 1999 and broadly expressed in the organism. As the only known orexigenic hormone secreted in the periphery, it increases hunger and appetite, promoting food intake. Ghrelin has also been shown to be involved in various physiological processes being regulated in the central nervous system such as sleep, mood, memory and reward. Accordingly, it has been implicated in a series of psychiatric disorders, making it subject of increasing investigation, with knowledge rapidly accumulating. This review aims at providing a concise yet comprehensive overview of the role of ghrelin in psychiatric disorders. Ghrelin was consistently shown to exert neuroprotective and memory-enhancing effects and alleviated psychopathology in animal models of dementia. Few human studies show a disruption of the ghrelin system in dementia. It was also shown to play a crucial role in the pathophysiology of addictive disorders, promoting drug reward, enhancing drug seeking behavior and increasing craving in both animals and humans. Ghrelin's exact role in depression and anxiety is still being debated, as it was shown to both promote and alleviate depressive and anxiety-behavior in animal studies, with an overweight of evidence suggesting antidepressant effects. Not surprisingly, the ghrelin system is also implicated in eating disorders, however its exact role remains to be elucidated. Its widespread involvement has made the ghrelin system a promising target for future therapies, with encouraging findings in recent literature.