leptin and Alcoholism

Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.

Topics: Adaptation, Psychological; Alcoholism; Animals; Bone and Bones; Bone Density; Bone Development; Cigarette Smoking; Epigenesis, Genetic; Feeding Behavior; Glucocorticoids; Humans; Leptin; Models, Animal; Osteoporosis; Parathyroid Hormone; Prolactin; Risk Factors; Stress, Psychological

A significant challenge for understanding alcoholism lies in discovering why some, but not other individuals, become dependent on alcohol. Genetic, environmental, cultural, developmental, and neurobiological influences are recognized as essential factors underlying a person's risk for becoming alcohol dependent (AD); however, the neurobiological processes that trigger this vulnerability are still poorly understood. Hormones are important in the regulation of many functions and several hormones are strongly associated with alcohol use. While medical consequences are important, the primary focus of this review is on the underlying confluence of appetitive/feeding, reproductive and posterior pituitary hormones associated with distinct phases of alcoholism or assessed by alcohol craving in humans. While these hormones are of diverse origin, the involvement with alcoholism by these hormone systems is unmistakable, and demonstrates the complexity of interactions with alcohol and the difficulty of successfully pursuing effective treatments. Whether alcohol associated changes in the activity of certain hormones are the result of alcohol use or are the result of an underlying predisposition for alcoholism, or a combination of both, is currently of great scientific interest. The evidence we present in this review suggests that appetitive hormones may be markers as they appear involved in alcohol dependence and craving, that reproductive hormones provide an example of the consequences of drinking and are affected by alcohol, and that posterior pituitary hormones have potential for being targets for treatment. A better understanding of the nature of these associations may contribute to diagnosing and more comprehensively treating alcoholism. Pharmacotherapies that take advantage of our new understanding of hormones, their receptors, or their potential relationship to craving may shed light on the treatment of this disorder.

Topics: Adiponectin; Alcoholism; Central Nervous System Depressants; Ethanol; Ghrelin; Gonadal Steroid Hormones; Gonadotropins, Pituitary; Growth Hormone; Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Pituitary Hormones, Posterior; Substance Withdrawal Syndrome; Thyroid Hormones

There is growing evidence for a role of appetite-related peptides and volume-regulating hormones in alcoholism. In particular, recent evidence has suggested that hormones, such as ghrelin, insulin and leptin and volume-regulating hormones, could play a role in alcohol-seeking behaviour. The goal of this review is to discuss the results of recent preclinical and clinical investigations on this topic. The findings indicate that neuroendocrinological mechanisms are potentially involved in the neurobiology of alcohol craving. Accordingly, research on this topic could lead to possible development of new therapeutic approaches in the treatment of patients with alcohol problems.

Topics: Alcohol Drinking; Alcoholism; Animals; Appetite Regulation; Atrial Natriuretic Factor; Ghrelin; Humans; Insulin; Leptin; Motivation; Peptide Hormones; Societies, Medical; Vasopressins

Recent studies with endogenous neuropeptides have indicated their modulating role in the etiology of alcoholism. The role of endogenous opioids is relatively well known and there is growing evidence for a role of the appetite-regulating peptides leptin, ghrelin, neuropeptide Y, galanin, and orexins. It has been demonstrated that these peptides could also be involved in alcohol intake regulation and the occurrence of alcohol craving. Moreover, important significance is attached to corticotrophin-releasing factor, since an increased level of this peptide during alcohol withdrawal is responsible for the occurrence of anxiety behaviors. Knowledge of the processes tied with neuropeptides is needed in the search for more effective therapy for alcohol addiction as their actions could perhaps facilitate the search for new medicines which would adapt the therapy to the individual patient as well as contribute to increasing the effectiveness of alcohol addiction therapy.

Topics: Alcoholism; Brain; Galanin; Ghrelin; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Neural Pathways; Neuropeptide Y; Neuropeptides; Orexins; Receptors, Neuropeptide

Evidence is growing that appetite regulating peptides such as leptin and ghrelin, but also other hormones including prolactin are altered in alcoholism. The brain pro-opiomelanocortin (POMC) system which has important mediating roles in alcohol intake also has important functions in prolactin regulation and energy homeostasis. Furthermore, it has been demonstrated to be functionally integrated with leptin regulation. The satiety factor leptin seems to be counteracted by the gut-derived peptide ghrelin which increases hunger and food intake. Consequently, the POMC system may have a role in integrating regulation of alcohol effects and these seemingly disparate regulatory systems. The goal of this mini-review is to discuss the results of some recent investigations of the potential interactions of these systems with acute and chronic alcohol responses.

Topics: Alcohol Drinking; Alcoholism; Appetite; Brain; Drive; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Leptin; Motivation; Pituitary-Adrenal System; Pro-Opiomelanocortin; Prolactin; Substance Withdrawal Syndrome

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Leptin; Motivation; Neuropeptide Y; Neuropeptides; Rats; Substance Withdrawal Syndrome

As early as the beginning of the 20th century, changes in appetite and weight were recognized as important symptoms of severe psychiatric disorders. Particularly in the last decade, understanding of the regulation of appetite and weight has made major progress. In this context, the discovery of the adipose tissue hormone leptin, which signals the size of the peripheral fat stores to the CNS, was crucial. In addition, leptin is also involved in a number of CNS networks regulating behavior and thus of great importance for the pathophysiology of psychiatric disorders. Apart from sexual behavior, those networks include motor activity, sleep, and cognition. Moreover, leptin seems to be involved in the development and maturation of the brain. The present paper summarizes current studies which suggest that, in psychiatric disorders, leptin could be of importance not only for disease-associated or drug-related changes in appetite and weight but also for alterations in behavior and cognition.

Topics: Alcoholism; Animals; Appetite; Body Weight; Brain; Cognition; Humans; Leptin; Mental Disorders; Motor Activity; Schizophrenia; Sexual Behavior; Sleep

The neuroprotective effects of leptin and its role in addictive disorders has been highlighted by several recent studies. However, its potential effects on morphological alterations in alcohol dependence are yet to be investigated. Associations between leptin and the longitudinal courses of gray matter volume (GMV) and cortical thickness (CT) were investigated in N = 62 alcohol-dependent patients that underwent structural magnetic resonance imaging after a mean abstinence of 12 (baseline) and 27 days (follow-up) respectively. Blood samples were collected at baseline to determine leptin levels. A cohort of N = 74 healthy individuals served as a reference sample. At baseline, alcohol-dependent patients compared to healthy controls displayed smaller GMV in the insula, parts of the superior, middle and inferior frontal gyri and hippocampal regions and thinner CT in the insula, parts of the superior and middle frontal cortices, the lateral orbitofrontal cortex and parts of the occipital and lingual cortices that partially recovered during abstinence (p

Topics: Adult; Alcohol Abstinence; Alcoholism; Brain; Case-Control Studies; Cerebral Cortex; Cohort Studies; Female; Frontal Lobe; Germany; Gray Matter; Humans; Leptin; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Prefrontal Cortex; Prognosis; Recovery of Function

Patients with depression and alcohol use disorder frequently present with elevated markers of inflammation. Adipose tissue may function as a source for inflammation, yet the interplay between adiposity, alcohol use and depression has remained unknown. We examined 242 patients, referred to treatment for depressive symptoms, and followed for a period of 6 months. The assessments included screening for alcohol use and measurements of body mass index, serum adiponectin, leptin, resistin, progranulin, hs-CRP, IL-6 and MCP-1 at baseline and after 6 months of treatment. During follow-up, mean MADRS and AUDIT scores decreased significantly, whereas BMI increased. The changes in the levels of cytokines and adipokines were influenced by alcohol consumption and adiposity in a gender-dependent manner. The presence of AUD seemed to particularly influence the levels of cytokines. The levels of IL-6, hs-CRP, progranulin, and leptin differed between AUD and non-AUD groups at baseline, but no longer at 6 months. Baseline levels of leptin and resistin were higher in women and changes occurring in leptin, progranulin, and adiponectin were more notable in women. The data indicates significant gender-dependent interactions between depression, alcohol and mediators of inflammation, which should be considered in studies on the pathogenesis of depression and its comorbidities.

Topics: Adipokines; Adiponectin; Adiposity; Adult; Alcohol Drinking; Alcoholism; Biomarkers; Body Mass Index; Cytokines; Depression; Female; Follow-Up Studies; Humans; Inflammation; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Resistin

Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

Topics: Administration, Intravenous; Adult; Alcohol Drinking; Alcoholism; Central Nervous System Depressants; Central Nervous System Stimulants; Craving; Cues; Ethanol; Female; Ghrelin; Humans; Leptin; Male; Statistics as Topic

The aim of the current study was to analyze the relationships between plasma hormones, body weight parameters and stressful life events in anorexia nervosa (AN).. 72 females in the active phase of AN were evaluated. 52 healthy women constituted the control group. RIA kits were used to measure plasma hormone levels.. The concentrations of leptin, insulin, IGF-1, triiodothyronine, LH, FSH, estradiol, and testosterone were significantly lower and those of cortisol and growth hormone significantly higher in the AN than the control group. No hormonal differences between restrictive and binge-purging AN subtypes were found. Leptin, IGF-1, gonadotropins, and sex steroids correlated significantly negatively and growth hormone positively with total reduction of body weight or the degree of undernutrition. Associations were also found between lower insulin concentration and family violence, lower cortisol and psychiatric diseases in the family, higher testosterone and patient's alcohol or drug abuse.. The changed activity of the somatotropin-somatomedin, gonadal, and corticotrophin axes corresponds to the clinical stage of AN. Plasma IGF-1 seems to be the most sensitive and useful independent hormonal marker of cachexia.

Topics: Adult; Alcoholism; Anorexia Nervosa; Biomarkers; Cachexia; Divorce; Domestic Violence; Estradiol; Female; Hormones; Humans; Hydrocortisone; Insulin; Insulin-Like Growth Factor I; Leptin; Life Change Events; Nutritional Status; Parent-Child Relations; Sibling Relations; Substance-Related Disorders; Testosterone; Young Adult

The appetite regulating peptide leptin has recently been associated with craving for alcohol and lifetime ethanol intake. However, effects of anti-craving drugs on leptin have not been studied until now. The objective of our study was to test the hypothesis whether leptin plasma concentration in abstinent alcohol addicts during treatment with naltrexone vs. acamprosate is associated with abstinence duration and craving for alcohol. Leptin plasma concentration was measured in 160 recently detoxified alcohol addicts during a double-blind, placebo-controlled relapse prevention trial with naltrexone vs. acamprosate vs. naltrexone plus acamprosate. During placebo treatment, increasing leptin plasma concentration was observed, whereas during combined treatment with naltrexone and acamprosate, leptin decreased significantly. The change from baseline of leptin plasma levels after weeks 4, 8 and 12 was inversely correlated with duration of abstinence and, after 4 weeks, positively correlated with self-rated craving. In summary, the study presents first evidence for an association of increasing leptin plasma concentrations with relapse to renewed alcohol intake in detoxified alcoholics. Moreover, there are hints for an interaction between pharmacological anti-craving treatment, plasma concentration of leptin, and abstinence duration.

Topics: Acamprosate; Adult; Alcohol Deterrents; Alcoholism; Double-Blind Method; Female; Humans; Leptin; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Placebos; Recurrence; Taurine

Topics: Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Alcoholism; Atrial Natriuretic Factor; Ethanol; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Male; Middle Aged; Outpatients; Self Administration; Self Disclosure; Substance Withdrawal Syndrome; Time Factors

Association between leptin plasma levels and alcohol craving has been seen previously. This study aims to research this correlation in a different population while comparing this correlation with respect to hyper-excitable state of alcohol withdrawal.. 25 patients of alcohol dependence were assessed for withdrawal symptoms and craving for alcohol. Leptin levels were measured on 1. Leptin levels [t (38) = 2.95, p = 0.005] was significantly higher in alcohol dependent patients. Levels had no significant correlation with alcohol withdrawal scores [Leptin/BMI and CIWA Ar: r = 0.18, p = 0.40 on day 1] but had positive correlation with craving scores [Leptin/BMI and PACS: r = 0.684, p = 0.001].. This study shows that leptin, known for balancing the energy homeostasis of body, also seem to play a role in pathways of drug dependence and craving. This relation is independent of stress hormone axis.

Topics: Alcoholism; Craving; Ethanol; Humans; Leptin; Substance Withdrawal Syndrome

Alcohol dependence affects metabolic processes. Further research is needed to apply this knowledge clinically. In this study, possible differences in serum lipids and/or leptin activities between alcohol-dependent in-patients and healthy controls and possible associations with alcohol-related blood parameters and with prospective outcomes in alcohol dependence were assessed sex-specifically.. We measured and compared (median) serum lipids (triglycerides and total, HDL, and LDL cholesterol) and leptin activities (leptin, soluble leptin receptor [ObRe], and free leptin index) in 200 (males 56.5 %) early-abstinent alcohol-dependent in-patients and 240 (males 55.4 %) healthy controls and assessed alcohol-related readmissions during a 24 -month post-inclusion period.. Male patients showed higher HDL cholesterol (61 versus 48 mg/dl), lower LDL/HDL ratios (2.06 versus 3.04), and lower free leptin index (0.30 versus 0.59) at study inclusion compared to healthy controls. In patients, ObRe levels were higher than in controls and decreased from inclusion to the second study-visit (at median 5 days later; males: 16.7-13.8 versus 11.0 ng/ml; females: 17.0-13.4 versus 12.1 ng/ml). The free leptin index increased between the two time points in females (0.80 versus 1.20). Lipids and leptin activities correlated with carbohydrate-deficient transferrin levels and liver enzyme activities. None of the serum parameters were significantly associated with alcohol-related readmissions.. Our data support that serum lipid levels and leptin activities are involved in alcohol dependence. The parameters appear as possible indirect biomarkers for alcohol dependence.

Topics: Adult; Alcoholism; Biomarkers; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Female; Humans; Leptin; Lipids; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Receptors, Leptin

The goal of this study was to determine whether the plasma leptin, nesfatin-1, cortisol, brain-derived neurotrophic factor (BDNF), and inflammatory cytokines could be used as potential biomarkers for the degree of craving in the alcohol-dependent patients after 1 month of abstinence. A total of 83 patients with alcohol use disorder (AUD) and 61 healthy subjects were assessed. Patients with AUD were selected from Department of Material Dependence, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. The Alcohol Urge questionnaire Scale (AUQ) was used to evaluate the extent of craving for alcohol, and the Michigan Alcoholism Screening Test (MAST), the Fagerstrom Test for Nicotine Dependence (FTND), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) were also assessed in patients with AUD. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the measurement of plasma leptin, nesfatin-1, cortisol, BDNF, Interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) levels. Compare with healthy controls, the average leptin, leptin/BMI, IL-6, CRP, and TNF-α levels in patients with AUD were significantly increased, while the BDNF levels were significantly decreased. Moreover, the partial correlational analysis showed that the AUQ scores of the alcohol-dependent patients were positively correlated with the plasma leptin levels (

Topics: Adolescent; Adult; Aged; Alcohol Abstinence; Alcoholism; Biomarkers; Brain-Derived Neurotrophic Factor; C-Reactive Protein; Case-Control Studies; Craving; Humans; Leptin; Male; Middle Aged; Nucleobindins; Young Adult

Leptin and ghrelin and a "cross-talk" between both hormones were implicated in the pathophysiology of alcohol dependence, both modulating alcohol craving and drug-seeking. To date, the neurobiological mechanisms underlying those effects are still little-known. We thus investigated the effect of leptin and ghrelin on alcohol cue-induced brain response, alcohol craving and relapse risk in alcohol-dependent subjects. Seventy abstinent alcohol dependent individuals underwent a functional magnetic resonance imaging (fMRI) alcohol cue-reactivity task and patients` alcohol craving was assessed. Plasma levels of leptin, total and acylated, active ghrelin were measured prior to the fMRI session. Additionally, relapse data was collected during a three-month follow-up. Associations between hormone levels, mesolimbic cue-reactivity, alcohol craving and relapse risk were tested. Leptin levels showed a significant negative association to alcohol cue-induced brain response in the striatum and alcohol craving. In addition, there was a significant effect of leptin on time to first heavy relapse in which higher leptin levels predicted longer times to first heavy relapse. Moreover, positive associations between acylated ghrelin and increased cue-reactivity in bilateral insulae as well as increased craving for alcohol during the fMRI task were revealed. Leptin and acylated ghrelin show opposing effects on mesolimbic cue-reactivity and alcohol craving. We suspect that the reduced striatal cue-reactivity might be the neurobiological correlate of leptin's effect on relapse-risk. The reported results further support the relevance of appetite regulating hormones in the pathophysiology of addiction and their potential role as future treatment targets.

Topics: Adolescent; Adult; Aged; Alcohol Abstinence; Alcohol Drinking; Alcoholism; Brain; Chronic Disease; Conditioning, Psychological; Craving; Cues; Ethanol; Ghrelin; Humans; Leptin; Magnetic Resonance Imaging; Middle Aged; Nerve Net; Recurrence; Young Adult

Appetite-regulating peptides, such as leptin, are linked to craving and have been in the focus of alcohol dependence research for years. The objective of our study was to investigate the dynamics of leptin gene promoter methylation during alcohol withdrawal and specific treatment in a rodent (rat) model for alcohol dependence. DNA methylation was measured using direct bisulfite sequencing at 0 h, 24 h, and 6 days of alcohol withdrawal as well as after treatment with alpha-melanocyte-stimulating hormone (alpha-MSH), Beta-Endorphin, or saline. We found significantly lower methylation levels in alcohol-consuming animals compared to alcohol-naïve animals. During 6 days of alcohol deprivation, this difference in methylation vanished. Leptin methylation of the alpha-MSH-treated group and 6 days alcohol-deprived animals was significantly higher than that in saline-treated animals, possibly indicating compensatory effects of the treatment. Our results further expand on previous findings from human studies that explain leptin's role in bridging the gap between alcohol consumption and appetite regulation.

Topics: Alcoholism; alpha-MSH; Animals; beta-Endorphin; DNA Methylation; Ethanol; Leptin; Male; Promoter Regions, Genetic; Rats; Substance Withdrawal Syndrome

Liver transplantation is the only curative treatment available for patients with end-stage alcoholic liver disease. As different studies showed a significant association between leptin plasma levels, gene methylation patterns and the extent of craving in alcohol-dependent patients, we investigated the effect of liver transplantation on leptin expression and promoter methylation.. The present study shows that in alcohol-dependent patients with liver cirrhosis leptin is significantly higher before liver transplantation and decreases significantly after transplantation. Alcohol-dependent patients on the waiting list had significantly higher leptin promoter methylation values than patients who underwent liver transplantation for other reasons than alcoholic liver disease.. Only plasma of 118 and peripheral blood mononuclear cells of 121 patients were used: healthy controls (C, n = 24/22), alcohol-dependent patients without ethyltoxic liver cirrhosis (AD, n = 24/22), patients after liver transplantation for other reasons than ethyltoxic liver cirrhosis (C-Tx, n = 18/21), alcohol-dependent patients suffering from ethyltoxic liver cirrhosis on the transplantation waiting list (Pre-Tx, n = 30/28) and patients with prior ethyltoxic liver cirrhosis after liver transplantation (Post-Tx, n = 22/28).. Leptin protein was significantly elevated in the pre-transplantation cohort when compared to post-transplantation and alcohol-dependent cohorts. Furthermore, leptin promoter methylation was higher in ethyltoxic patients before transplantation compared to non-ethyltoxic patients after transplantation, but not when compared to ethyltoxic patients after transplantation. C-Tx had lower methylation values than all other groups except for Post-Tx.. Our study outlines the role of leptin protein levels as a marker for AD-related liver damage, contrasting it from AD without severe liver damage. With regard to the results of the methylation analysis, inflammation of the liver appears to cause mechanisms of leptin regulation to deviate from transcriptional regulation. Our data also suggest that leptin regulation is altered in ethyltoxic liver disease when compared to liver cirrhosis caused by other pathologies.

Topics: Adult; Aged; Alcoholism; Biomarkers; Biomedical Research; Female; Forecasting; Gene Expression; Humans; Leptin; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Methylation; Middle Aged

Leptin has been suggested to be involved in the pathophysiology of addictive disorders via modulation of mesolimbic reward pathways. Previous studies in patients with substance use disorders (alcohol, tobacco, cocaine) found positive correlations of leptin blood levels with craving. Here, we investigated leptin blood levels in patients with non-substance related addictive disorders such as pathological gambling (PG) and internet gaming disorder (IGD) in comparison to patients with alcohol use disorder (AUD) and healthy controls. Plasma levels of leptin were measured in male patients with PG (n = 14), male patients with IGD (n = 11), male patients with AUD (n = 39) and male healthy controls (n = 12). Additionally, correlation analyses with blood levels of HPA axis hormones were performed. Leptin plasma levels of patients with PG, IGD or AUD and healthy controls did not differ significantly across groups. In patients with PG, leptin plasma levels were correlated with copeptin, a surrogate for arginine vasopressin. Our findings do not suggest an involvement of leptin in abstinent patients with AUD or in patients with active IGD. In patients with active PG, leptin blood levels were not related to craving for gambling, but leptin might be involved in PG via an interaction with the HPA axis.

Topics: Adult; Alcoholism; Behavior, Addictive; Gambling; Glycopeptides; Humans; Internet; Leptin; Male; Middle Aged; Reward; Video Games; Young Adult

Different studies have described evidence for an association between leptin serum levels and craving in alcohol dependent patients. As leptin expression is regulated by DNA methylation we investigated changes of DNA methylation of the LEP gene promoter region in alcohol dependent patients undergoing withdrawal. Results show that low methylation status is associated with increasing serum leptin levels and elevation of craving for alcohol in the referring patients group. These findings point towards a pathophysiological relevance of changes in DNA methylation of the LEP gene promoter region in alcohol dependence.

Topics: Adult; Alcoholism; Craving; DNA Methylation; Female; Genetic Association Studies; Humans; Leptin; Male; Middle Aged; Promoter Regions, Genetic; Substance Withdrawal Syndrome

There is growing evidence that white adipose tissue is an important contributor in the pathogenesis of alcoholic liver disease (ALD). We investigated serum concentrations of total adiponectin (Acrp30), leptin, and resistin in patients with chronic alcohol abuse and different grades of liver dysfunction, as well as ALD complications.. One hundred forty-seven consecutive inpatients with ALD were prospectively recruited. The evaluation of plasma adipokine levels was performed using immunoenzymatic ELISA tests. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications.. Acrp30 and resistin levels were significantly higher in patients with ALD than in controls. Lower leptin levels in females with ALD compared to controls, but no significant differences in leptin concentrations in males, were found. High serum Acrp30 level revealed an independent association with advanced liver dysfunction, as well as the development of ALD complications, that is, ascites and hepatic encephalopathy.. Gender-related differences in serum leptin concentrations may influence the ALD course, different in females compared with males. Serum Acrp30 level may serve as a potential prognostic indicator for patients with ALD.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Alcoholism; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Leptin; Liver; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Multivariate Analysis; Prognosis; Prospective Studies; Resistin; Sex Factors

Alcohol use affecting the risk of type 2 diabetes mellitus (T2DM) is poorly identified as well as the role of brain-derived neurotrophic factor (BDNF), ghrelin, and leptin in alcohol dependence with T2DM. We tested the hypothesis that alcohol abstinence affects diabetes-related factors and BDNF, ghrelin, and leptin secretions in alcohol-dependent patients with glucose intolerance.. A total of 64 male alcohol-dependent patients were classified into normal glucose tolerance (NGT), pre-diabetes mellitus (pre-DM), and diabetes mellitus (DM) groups according to a 75-g oral glucose tolerance test (OGTT). All participants got alcohol dependence rehabilitation treatment for 30 days, and then we compared changes in BDNF, ghrelin, and leptin between pre- and post-alcohol abstinence.. After alcohol abstinence, both pre-DM and DM groups had significantly decreased levels of fasting glucose. All 3 groups exhibited elevated ghrelin levels and reduced leptin levels, but BDNF levels were significantly increased only in the pre-DM group. The pre-DM group had large increases in BDNF and ghrelin levels compared with those of the NGT group. Moreover, decreases in homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose, and leptin levels in the DM group were larger than those in the NGT group.. Alcohol abstinence might influence diabetes-related factors of alcohol-dependent patients with glucose intolerance. Further, BDNF, ghrelin, and leptin differently affect this improvement, depending on the stage of DM. In the pre-DM group, elevated BDNF and ghrelin levels are likely to influence insulin sensitivity, insulin resistance, and fasting glucose levels. Further, reduced leptin levels after abstinence might be related to improved glucose kinetics in patients with diabetes.

Topics: Adult; Alcoholism; Biomarkers; Brain-Derived Neurotrophic Factor; Ghrelin; Glucose Intolerance; Humans; Leptin; Male; Middle Aged; Temperance

The issue of leptin as a putative state marker of alcohol use and its role in craving has been raised in the last few years. Recently, a strong GABA-ergic modulation of leptin was postulated. The aim of the pilot study was to examine leptin levels in correlation with the strongly GABA-mimetic active substance clomethiazole. The main hypothesis was that higher doses of the strong GABA-mimetic clomethiazole are positively correlated with higher leptin levels.. Twenty-eight alcohol-dependent patients (3 females, median age 36 years) undergoing alcohol withdrawal were included. In 18 patients with and 10 without clomethiazole, serum leptin was analyzed at day 1 and day 7 of alcohol withdrawal. Both groups did not differ by age, BMI, or alcohol use characteristics.. In the clomethiazole group, significant correlations were found between leptin levels at day 1 and clomethiazole dose (p = 0.004), clomethiazole and leptin at day 1/BMI (p = 0.009) and leptin at day 1 and clomethiazole/body surface (p = 0.006). Furthermore, patients with higher clomethiazole doses demonstrated significant higher leptin levels at day 1 (p = 0.044) and day 7 (p = 0.046).. Our pilot data show a strong association between leptin levels and clomethiazole doses, thus supporting further research.

Topics: Adult; Alcoholism; Anticonvulsants; Chlormethiazole; Dose-Response Relationship, Drug; Female; GABA Modulators; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Pilot Projects; Statistics, Nonparametric; Substance Withdrawal Syndrome; Time Factors

A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency.. In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA](n)) are linked to alcohol addiction and craving.. We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p < 0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p < 0.05) and lower levels of craving (p < 0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p < 0.05). No effects were found for A49T or (TA)(n).. These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adult; Alcoholics; Alcoholism; Analysis of Variance; Aromatase; Behavior, Addictive; Case-Control Studies; Chi-Square Distribution; Gene Frequency; Genetic Predisposition to Disease; Humans; Leptin; Linear Models; Male; Membrane Proteins; Middle Aged; Minisatellite Repeats; Phenotype; Polymorphism, Single Nucleotide; Recurrence; Risk Factors; Substance Withdrawal Syndrome; Temperance

Most physiological studies interested in alcohol-dependence examined ethanol as a pharmacological agent rather than a nutrient. We conducted two studies, which assessed the metabolic and endocrine factors involved in the regulation of alcohol and nutrient intake in alcohol-dependent (AD) subjects. We also examined the potential role of a disruption in energy balance in alcohol-dependence.. In Study-1, quantitative dietetic interviews of eating and drinking habits were conducted with 97 AD subjects. The population was split around a median alcohol intake value of 12.5 kcal/kg/day. The results showed that the "low alcohol" drinking AD subjects had high Body Mass Index (BMI) and Fat Mass (FM) and alcohol intake was compensated for by a decrease in non-alcoholic intakes. "High alcohol" drinking AD subjects, on the other hand, had low BMI and FM and the total caloric intakes were largely above norms. In Study-2, 24 AD inpatients were submitted to dietetic interviews, calorimetry and blood samplings for the measurement of biomarkers of the regulation of metabolism and satiety, on day 2, 5 and 16 of abstinence. These patients were compared with 20 controls matched for age and gender. We observed in AD patients an increase in cortisol, leptin and PYY plasma levels and a decrease in ghrelin, which might explain the observed decrease in non-alcoholic intakes. However, alcoholic and non-alcoholic intakes correlated positively with basal metabolism and negatively with leptin and leptin/BMI.. For individuals consuming below 12.5 kcal/kg/day of alcohol, alcohol intake is compensated for by a decrease in non-alcoholic nutrient intakes, probably due to changes in metabolic and satiety factors. For individuals consuming above 12.5 kcal/kg/day of alcohol, alcohol accelerates metabolism and decreases fat mass and leptin levels, and the total caloric intake largely exceeds norms. A dual model for regulation of energy intake in AD subjects is proposed.

Topics: Adult; Alcohol Drinking; Alcoholism; Basal Metabolism; Body Composition; Body Mass Index; Calorimetry; Eating; Energy Intake; Female; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Peptide YY; Satiation; Surveys and Questionnaires; Temperance

There have been lots of studies about the relationship between chronic use of alcohol and the development of type 2 diabetes mellitus (T2DM). Chronic use of alcohol can be affected by the altered level of ghrelin and leptin which regulate food-seeking behavior having similar mechanism of controlling alcohol-craving behavior. Those peptides are known to be correlated with T2DM. Ghrelin and leptin also have been regarded as possible regulators of glucose metabolism and insulin function. Hence, there is the possibility that ghrelin and leptin can be related with deteriorated pathophysiology of T2DM in alcoholic patients.. Patients with alcohol dependence diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) underwent an 75 g oral glucose-tolerance test (OGTT), to classify them to normal glucose tolerance (NGT, n = 52), pre-diabetes including impaired glucose tolerance (IGT), impaired fasting glucose level (IFG) and combination of IGT and IFG (Pre-DM, n = 26) and T2DM (n = 24) groups. Fasting plasma ghrelin and leptin levels were compared among groups.. There was no difference of ghrelin concentration among the groups but the leptin concentration was significantly different between NGT and T2DM group (p < 0.05). Increased leptin levels were significantly correlated with body mass index (BMI), insulin level, and insulin resistance.. Chronic alcohol drinking might produce leptin resistance which makes leptin significantly correlated with fasting insulin concentration and insulin resistance. Therefore, we suppose that increased level of leptin by chronic alcohol use could be one of the main mechanisms that develop insulin resistance in alcoholic patients.

Topics: Alcoholism; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Ghrelin; Humans; Insulin Resistance; Leptin; Male; Middle Aged

Alcoholism is associated with alterations of the hypothalamus-pituitary-gonadal hormone axis. We recently reported a leptin-mediated relation between the CAGn polymorphism of the androgen receptor and craving during alcohol withdrawal. This study investigated whether the TTTAn polymorphism of the aromatase (CYP19A1) is equally linked to craving. An association between TTTAn and compulsive craving (p=0.029) was revealed in our sample of 118 male alcohol addicts at day of hospital admission. Genotype-dependent subgroups showed differences in that the patients with short alleles suffered from lower compulsive craving during withdrawal than those with the longer alleles (p=0.027). The additional inclusion of leptin revealed no further significant association in the present study. Our finding is a further step on the way to elucidate the genesis of craving for alcohol with its extensive underlying interactions of different genetic and non-genetic factors. Future investigations should enrol women and consider sex hormone levels for further clarification of the observed TTTAn-craving relationship.

Topics: Alcoholism; Aromatase; Case-Control Studies; Compulsive Behavior; Feeding and Eating Disorders; Feeding Behavior; Gene Frequency; Genotype; Humans; Leptin; Male; Middle Aged; Patient Admission; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Sex Factors; Substance Withdrawal Syndrome

Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations reaching levels that have measurable affects on physiology and/or behavior. The present study determined if increased ethanol drinking associated with DID procedures may be motivated by caloric need rather than by the postingestive pharmacological effects of ethanol. To this end, food availability was manipulated or mice were given peripheral administration of orexigenic or anorectic agents during DID procedures.. C57BL/6J had 2-hours of access to the 20% (v/v) ethanol solution beginning 3-hours into the dark cycle on days 1 to 3, and 4-hours of access to the ethanol bottle on day 4 of DID procedures. In Experiment 1, the effects of food deprivation on ethanol consumption during DID procedures was assessed. In Experiments 2 and 3, mice were given intraperitoneal (i.p.) injection of the orexigenic peptide ghrelin (0, 10 or 30 mg/kg) or the anorectic protein leptin (0 or 20 microg/g), respectively, before access to ethanol on day 4 of DID procedures. In Experiment 4, hourly consumption of food and a 0.05% saccharin solution were assessed over a period of hours that included those used with DID procedures.. Consistent with previous research, mice achieved blood ethanol concentrations (BECs) that ranged between 100 and 150 mg% on day 4 of DID experiments. Neither food deprivation nor administration of orexigenic or anorectic compounds significantly altered ethanol drinking with DID procedures. Interestingly, mice exhibited their highest level of food and saccharin solution consumption during hours that overlapped with DID procedures.. The present observations are inconsistent with the hypothesis that C57BL/6J mice consume large amounts of ethanol during DID procedures in order to satisfy a caloric need.

Topics: Alcohol Drinking; Alcoholism; Animals; Appetite Depressants; Appetite Stimulants; Darkness; Disease Models, Animal; Energy Intake; Ethanol; Feeding Behavior; Food Deprivation; Ghrelin; Injections, Intraperitoneal; Leptin; Male; Mice; Mice, Inbred C57BL; Saccharin

Recent studies have described an association of leptin serum levels and craving in alcohol dependent patients. The aim of the present study was to investigate a large patients' sample using a power-based statistical analysis. We included 156 male and 33 female patients suffering from alcohol dependence admitted for detoxification treatment. Leptin serum levels were measured using a commercial ELISA kit. The Obsessive Compulsive Drinking Scale (OCDS) was used to assess alcohol craving at admission. For both genders Spearman's correlation revealed significant results. These findings could be confirmed using multiple linear regression models (males: r=1.881, t=4.338, p<0.001; females: r=6.160, t=5.793, p<0.001) with a power of 1.00. In contrast to previous results describing an association only in female patients, this power-based analysis shows that leptin is associated with alcohol craving in both genders.

Topics: Adult; Alcohol Drinking; Alcoholism; Body Mass Index; Female; Humans; Leptin; Male; Middle Aged; Obsessive Behavior

A role of appetite-regulating peptides like leptin and ghrelin in the neurobiology of alcohol craving has been proposed by several studies. Aim of this analysis was to search for differences regarding an association between these peptides and alcohol craving with respect to different subtypes and beverage consumption patterns in patients with alcohol dependence.. We analyzed a sample of 188 patients at admission for alcohol detoxification regarding leptin and ghrelin (n=117) serum levels. Craving was measured using the Obsessive Compulsive Drinking Scale (OCDS). Patients were classified according to Lesch's typology of alcohol dependence and according to their preferred type of alcoholic beverage (beer, wine, spirits).. Using general linear models to analyze a possible interaction between subtypes and leptin/ghrelin levels with respect to craving, we found a significant positive association for leptin in patients of Lesch's types 1 and 2, and in patients consuming beer or wine. Ghrelin levels showed a significant trend regarding an association with craving in patients of Lesch's type 1. In the other subgroups we found no significant results.. Our findings show that appetite-regulating peptides may be of special importance regarding alcohol craving in subtypes of patients. This may explicate at least in part previous contradictory findings.

Topics: Adult; Alcohol Drinking; Alcoholism; Appetite Regulation; Female; Ghrelin; Humans; Leptin; Linear Models; Male; Middle Aged; Peptide Hormones

Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity.. Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2)-stimulated NK activity, and concanavalin A-stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n = 27) and age- and gender-matched controls (n = 34).. As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p = 0.055). In the total sample, leptin predicted NK activity (beta = 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n = 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone.. These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.

Topics: Adult; Alcoholism; Analysis of Variance; Humans; Immunity, Cellular; Leptin; Male; Middle Aged; Temperance

The growing number of studies examining the relationship between suicide and lipid metabolism are based upon studies suggesting that cholesterol-lowering procedures may increase the risk of death due to suicide or impulsive-aggressive behavior. Leptin seems to be strongly associated with lipid metabolism. In the present study, serum total cholesterol and leptin levels were compared in 24 suicide attempters and 24 healthy controls. The patients with suicide attempts had significantly lower serum cholesterol and leptin levels than controls. There was a positive correlation between cholesterol and leptin levels in both groups. Our results suggest that suicide attempts seem to be associated with decreased serum cholesterol and leptin levels.

Topics: Adult; Alcoholism; Bipolar Disorder; Borderline Personality Disorder; Cholesterol; Depressive Disorder, Major; Female; Humans; Leptin; Male; Mental Disorders; Middle Aged; Schizophrenia; Suicide, Attempted

Malnutrition seen in chronic alcoholics is partly due to reduced energy intake. Leptin is a peptide hormone implicated in the regulation of appetite and expenditure of energy. The prevalence and significance of abnormal circulating leptin levels in alcoholics, as well as the relationship of these levels with nutritional status, liver disease, and ethanol consumption, remain uncertain.. Serum leptin levels were measured in 60 active asymptomatic alcoholics, 20 active alcoholics with cirrhosis of the liver, 20 abstinent alcoholics, and 60 controls. Nutritional status and ethanol consumption also were assessed.. In the control group, circulating leptin levels (mean 4.7+/-0.3 microg/liter) correlated with body fat stores. Despite showing a lower fat area of the arm, active alcoholics had significantly higher leptin levels than the controls (p < 0.001), regardless of the presence of cirrhosis. By contrast, none of the abstinent alcoholics showed hyperleptinemia. In the multivariate regression analysis, the fat area of the arm (p < 0.001), the lifetime ethanol consumption (p = 0.007), and the number of cigarettes smoked per day (p = 0.02) were found to be independent factors that influenced leptin levels in active alcoholics. After we adjusted for age, fat area of the arm, and tobacco consumption, a significant correlation was observed between lifetime consumption of ethanol and serum leptin concentrations (r = 0.36, p < 0.001).. Circulating leptin levels are increased in a dose-dependent manner in chronic alcoholism, regardless of nutritional status or the presence of compensated liver disease.

Topics: Adult; Alcoholism; Analysis of Variance; Biomarkers; Chi-Square Distribution; Dose-Response Relationship, Drug; Humans; Leptin; Male; Middle Aged; Multivariate Analysis; Nutrition Disorders; Nutritional Status; Regression Analysis; Temperance

Leptin has been shown to regulate food intake and energy expenditure. Because leptin acts via regulation of appetite, we studied the hypothesis that suggests leptin modulates craving for alcohol as well.. We studied leptin plasma concentrations (RIA) both in alcoholic subjects during inpatient detoxification (day 1: n = 78, day 14: n = 60) and in healthy control subjects (n = 30). To rule out interference with the activation of the HPA axis during alcohol withdrawal, we also evaluated cortisol plasma levels (RIA).. We found plasma leptin and cortisol elevated at onset of withdrawal, decreasing significantly up to day 14. Leptin (and the body-mass corrected ratio leptin/BMI) was highly correlated with self-rated craving. No correlations of craving with cortisol and BMI were observed.. We suggest that leptin may modulate withdrawal-induced craving in alcoholic subjects.

Topics: Adult; Alcoholism; Body Mass Index; Disruptive, Impulse Control, and Conduct Disorders; Ethanol; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Inactivation, Metabolic; Leptin; Male; Pituitary-Adrenal System; Radioimmunoassay; Substance Withdrawal Syndrome

Topics: Adult; Alcoholism; Animals; Behavior, Addictive; Body Mass Index; Body Weight; Ethanol; Humans; Hydrocortisone; Leptin; Radioimmunoassay; Rats; Substance Withdrawal Syndrome

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF-alpha expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF-alpha and cytokines [interleukin (IL)-6, IL-10, transforming growth factor-beta (TGF)-beta, IL-12, and interferon-gamma] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol-containing diets for 6 weeks. Cytokine expression in the ethanol-fed groups was compared with that of pair-fed controls rats that had received isocaloric amounts of a similar, ethanol-free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair-feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol-fed rats also expressed more leptin, a TNF-alpha-inducible mRNA that encodes an appetite-suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF-alpha as a potential mediator of the nutritional-metabolic aberrations that often accompany chronic alcohol intake, even in the absence of advanced liver disease.

Topics: Adipose Tissue; Alcoholism; Animals; Cytokines; Ethanol; Fatty Liver, Alcoholic; Leptin; Liver; Liver Diseases, Alcoholic; Macrophages; Monocytes; Proteins; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha