Psychiatric University Clinic and
2 Department Central Laboratory, University of Basel, Switzerland,
1 State Mental Hospital Bayreuth,
3 Mediagnost Inc., Reutlingen, Departments of Legal Medicine, Universities of
4 Ulm and
5 Erlangen and
6 Department of Clinical Chemistry, University of Magdeburg, Germany
Received 2 January 2003; in revised form 25 February 2003; in revised form 19 March 2003; accepted 24 March 2003
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ABSTRACT |
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INTRODUCTION |
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Rasmussen et al.(2002) have investigated the effects of chronic daily ethanol consumption, withdrawal and subsequent abstinence on adult rat forebrain opiomelanocortinergic activity. Plasma concentrations of corticosterone, testosterone and leptin were also altered by the daily ethanol/withdrawal treatment (consumption at night and withdrawal during the day) and by subsequent abstinence. Obradovic and Meadows (2002)
found that chronic ethanol consumption in mice increases the circulating level of leptin and that this is accompanied by altered expression of leptin-sensing molecules in the hypothalamus and peripheral adipose tissue. These results suggest that chronic ethanol intake (in mice) affects metabolism by altering the leptin system that regulates energy balance. There was also evidence from epidemiological studies that, among other lifestyle variables, alcohol consumption influences serum leptin levels (Wei et al., 1997
; Mantzoros et al., 1998
; Langiou et al., 1999). A decreased leptin renal excretion with increased leptin levels has been documented in alcoholic patients with advanced liver disease (Henriksen et al., 1999
). Song et al.(1999)
reported significantly higher production of interleukin 6 (IL-6), IL-10 and tumour necrosis factor-
(TNF
) in detoxified alcoholic patients without liver disease compared with healthy volunteers.
Recently the issue of leptin as a putative state marker of alcohol use has been raised by Nicolas et al.(2001). In a multivariate regression analysis they found that the fat area of the arm, the lifetime ethanol consumption and the number of cigarettes smoked per day were independent factors influencing leptin in alcohol-dependent patients regardless of nutritional status or the presence of a compensated liver disease. Circulating leptin levels were increased in a dose-dependent manner in active chronic alcoholism (Nicolas et al., 2001
). In contrast, Santolaria et al. (2003)
reported decreased leptin levels in alcoholic patients even after adjusting for the amount of body fat. Togo et al.(2000)
observed no association between the level of leptin and smoking or alcohol consumption in 708 Japanese men, although other studies (Wei et al., 1997
; Mantzoros et al., 1998
; Donahue et al., 1999
; Nicklas et al., 1999
; Chu et al., 2001
) reported a marked inverse effect of smoking on serum levels of leptin, offering a possible explanation for variation in body weight between smokers and non-smokers. Mantzoros et al.(1998)
found that circulating leptin concentrations independently and positively associated with alcohol intake, whereas other studies reported no (De Silva et al., 1998
; Lagiou et al., 1999
; Togo et al., 2000
) or opposite relationships (Donahue et al., 1999
).
Röjdmark et al.(2001) have shown that acute ethanol intake by healthy individuals is followed by decreased serum leptin levels. They speculate that alcohol might serve as an appetizer by decreasing leptin secretion, but additional studies are necessary to prove this hypothesis since previous studies have shown that leptin has a long-term rather than an acute effect on hunger. The data of the study of Hiney et al.(1999)
demonstrated that ethanol administration not only suppresses peripheral levels of leptin but also blocks its central action to facilitate luteinizing hormone secretion. The findings of Fujita et al.(2003)
suggest that ethanol-induced enhancement of appetite may, in part, result from leptin resistance transiently caused by ethanol to attenuate the leptin signal transduction. Surprisingly, leptin was significantly elevated in the offspring of paternally ethanol-exposed rats (after 2 months of ethanol feeding) (Emanuele et al., 2001
).
Kiefer et al. (2001a,b
,c
) tested the hypothesis that the application of exogenous leptin modulates voluntary alcohol consumption in mice. They found significantly elevated free-choice ethanol consumption after withdrawal in mice following intraperitoneal injection of 1 mg/kg leptin, but not during basal drinking (Kiefer et al., 2001c
). Therefore they suggest that leptin may enhance motivation for alcohol consumption in habituated mice after alcohol withdrawal. In another study on 20 alcohol-dependent patients, they raised the question of leptin as a possible modulator for craving (Kiefer et al., 2001b
). Leptin levels were found to be elevated in alcohol-dependent patients and correlated with craving as assessed by a visual analogue scale. In a recent study on 30 male alcoholic patients, Kiefer et al.(2002)
measured leptin and TNF
levels and craving the day following admission to hospital. The increased leptin levels correlated with craving.
The aim of the present study was to evaluate the potential of leptin as a state and trait marker and to rule out the role of current alcohol intoxication in the control of leptin levels.
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SUBJECTS AND METHODS |
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For comparison 27 blood samples of 18 abstinent addicted persons, matched for age (MannWhitney test: P = 0.118), gender (16 males, 2 females) and body mass index (BMI) (P = 0.143) were used.
Methods
Leptin was determined in samples on day 1 (immediately after hospitalization, when patients were still intoxicated with alcohol) and day 7 of withdrawal with a Human Leptin Standard RIA Kit (Mediagnost Inc., Reutlingen, Germany). Expected leptin levels were calculated with the formula:
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Body composition was measured using a bioimpedance device (Tanita Europe, Sindelfingen, Germany). Body surface was calculated according to the formula of Du Bois and Du Bois, 1916:
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Statistical analysis
For statistical analysis, SPSS 11 (SPSS Inc., Chicago, IL, USA) was used. Categorical variables not fitting the normal distribution were compared using non-parametric tests: the KruskalWallis for multiple variables and the MannWhitney U-test. Correlations presented are Spearman rank correlations.
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RESULTS |
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Significant correlation (Spearman rank correlation) was found between leptin and expected leptin levels, percentage fat body mass, BMI, GGT, blood alcohol concentration (BAC) and cigarettes smoked per day (Table 2). However, when using the ratio of leptin day 1/percentage body fat, no significant correlation was found with GGT, BAC and number of cigarettes.
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DISCUSSION |
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Furthermore we found, in contrast to others, no significantly elevated (Kiefer et al. 2001a,b
; Nicolas et al. 2001
) or decreased (Santolaria et al., 2003
) leptin levels at the beginning of the detoxification. However, we compared days 1 and 7, whereas others (Kiefer et al., 2001a
,b
; Santolaria et al., 2003
) compared days 1 and 14. On the other hand, we found no difference between the measured levels of detoxification patients and abstainers, or compared with expected levels. Santolaria et al.(2003)
reported decreased circulating serum leptin levels in chronic alcoholic patients without acute intoxication. This decrease was considered by the authors to be a consequence of a low fat mass. Although the data presented to date are inconsistent even as to whether leptin levels are elevated, normal or decreased in chronic alcoholism, it seems promising to consider the possibility of interactions between chronic and acute effects that could, based on the current state of knowledge, be synergistic, neutral or antagonistic. Clearly, the limitation of our study is that we cannot differentiate these possible effects at admission to hospital. However, we should like to point out that no significant differences were found between day 1 and day 7 in alcoholic patients, the abstainers and the expected level, which could possibly indicate that a potential influence is rather limited or antagonistic effects are seen at admission with acute intoxication being superimposed on a longer lasting intake of alcohol. The negative correlation with nicotine, as previously reported in other studies (Mantzoros et al., 1998
; Donahue et al., 1999
; Chu et al., 2001
), might be explained partly by the following: those smoking the most have the lowest percentage of body fat and thus the lowest leptin levels. Santolaria et al.(2003)
, too, found that smokers had a lower fat mass that non-smokers and leptin depends mainly on fat mass, but not on smoking habit itself.
An aspect to be further examined is the fact that alcohol withdrawal can be understood as acute stress. Alcohol-dependent patients have an impaired cortisol response to stress, indicating dysregulation in the extrahypothalamic systems responsible for activating cortisol secretion in response to stressor exposure (Errico et al., 2002). The endocrine effects of stress for alcoholic patients during the withdrawal phase have been demonstrated. Another important question concerns the association of plasma leptin level with cortisol, which is known as a metabolic regulator of various stress-related factors, during alcohol withdrawal. No significant relationship between plasma cortisol and leptin, BMI or the leptin/BMI ratio was detected in either the alcoholic or control subject groups in the study of Kiefer et al. (2001a)
. There is no striking evidence that the phase of alcohol withdrawal, treated with clomethiazole, produces measurable endocrinological stress (Rasmussen et al., 2000
). Also, it is known that stress-related hormones in alcoholic patients are altered for longer periods, even weeks after withdrawal (Baumgartner et al., 1994
; Ehrenreich et al., 1997
). However, even if alcohol withdrawal treated by clomethiazole increased cortisol, a possible relationship between the neurobiology of these two systems (cortisol and leptin) is contradictory (Kain et al., 1999
; Wallace et al., 2000
; Modan-Moses et al., 2001
; Schafroth et al., 2001
).
There are results indicating that glucocorticoids enhance the amplitude of leptin diurnal rhythm, which is consistent with previous findings showing that glucocorticoids increase leptin secretion (Nishiyama et al., 2000). Corticotropin releasing hormone hyperactivity persists after 12 weeks of alcohol withdrawal in alcoholic patients, especially with co-morbid disorders (Ehrenreich et al., 1997
). To assess the action of this hormone on brain reward circuitry, changes in the rewarding effect of lateral hypothalamic stimulation were measured after leptin administration by Fulton et al.(2000)
. Kiefer et al. (2001c
, 2002
) have explained the association of increased alcohol craving with higher plasma leptin in their alcoholic sample with the reward theory of Fulton et al.(2000)
. Other neurobiological factors, like GABAergic mechanisms, might also contribute to the complex mechanisms regulating leptin levels.
From a theoretical viewpoint, as well as from preclinical and clinical results, the idea of an influence of leptin on alcohol consumption, or of alcohol on leptin levels, mediated by inflammatory processes including TNF is striking. Further studies under well-defined conditions are needed to address these points.
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FOOTNOTES |
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