Eat Weight Disord (2014) 19:3–10 DOI 10.1007/s40519-013-0094-z
REVIEW
Adiponectin in eating disorders Rami Bou Khalil • Charline El Hachem
Received: 9 September 2013 / Accepted: 19 December 2013 / Published online: 28 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Purpose To elucidate the possible role of adiponectin, an adipokine secreted by white adipose tissue that plays an important role in the neuromodulation of food intake, in the pathogenesis of eating disorders. Methods A comprehensive review of the available literature via MedLine is done using the term ‘‘adiponectin’’ in association with one of the following terms: ‘‘anorexia nervosa’’, ‘‘bulimia nervosa’’, ‘‘binge eating disorder’’ or ‘‘eating disorders’’. Results The majority of studies evaluating serum adiponectin levels in patients with eating disorders show that serum adiponectin levels are increased in patients with anorexia nervosa. After refeeding, adiponectin levels tend to rejoin the levels of healthy individuals. Data concerning serum adiponectin levels in patients with bulimia nervosa show that these levels can be equal, higher or lower than those found in healthy controls and lower than those found in anorexia nervosa patients. Binge eating disorder is accompanied with lower serum adiponectin levels than normal. Adiponectin receptor type 1 seems to be more related to the central pathological effect of adiponectin on eating behavior. Conclusion The potential role that plays adiponectin in the pathogenesis of eating disorders needs to be elucidated by further studies.
R. Bou Khalil (&) C. El Hachem Saint Joseph University, Beirut, Lebanon e-mail: [email protected] R. Bou Khalil Psychiatric Hospital of the Cross, P.O. box: 60096, Jalledib, Lebanon
Keywords Adiponectin Eating disorders Anorexia nervosa Bulimia nervosa Binge eating disorders
Introduction Adiponectin is a 30-kDa protein mainly secreted by the adipose tissue and reaches a plasma concentration of 2–10 lg/ml in humans [1]. It is a 244-amino-acid protein composed of an amino-terminal signal peptide followed by a species-specific variable domain, a collagenous domain of 22 Gly-X–Y repeats, and a carboxyl-terminal globular domain that is similar to the complement factor C1q and structurally similar to tumor necrosis factor-a (TNFa) [2– 4]. In the blood circulation, adiponectin exists as multiple isoforms: a low-molecular-weight (LMW) form, a middlemolecular-weight (MMW) form, and a high-molecularweight (HMW) form [5]. Although adiponectin is secreted mainly by white adipose tissue, its expression was also found, in humans, in salivary gland epithelial cells, bone marrow, osteoblasts, fetal tissue, myocytes and cardiomyocytes [6]. The serum concentrations of adiponectin, unlike most of the other adipokines, are inversely correlated with body mass index (BMI) and visceral fat accumulation [7–9]. Three adiponectin receptors have been identified: adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) and, more recently, T-cadherin [10]. Adiponectin primarily mediates its insulin-sensitizing effects through the sequential activation of adenosine monophosphate-activated protein kinase (AMPK), p38 mitogenactivated protein kinase (MAPK) and peroxisome proliferator activated receptor-alpha (PPARa) [11]. Accumulating evidence suggests that adipose-tissue derived hormones such as adiponectin may act as key neuromodulators of food intake, energy expenditure and reproductive
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functions. Individuals with high concentrations of this protein are less likely to develop type 2 diabetes than those with low concentrations, thus supporting the hypothesis that adiponectin may play a role in the progression from obesity to type 2 diabetes [12]. There is a disagreement about the exact role of adiponectin in the brain. However, the wide distribution of adiponectin receptors, the local production of adiponectin, and the release of somatotrophs and gonadotrophs from rat pituitary cell cultures strengthen the hypothesis that adiponectin has a real effect in the brain [13]. In this article the role of adiponectin in eating disorders (ED) will be reviewed. Clinical studies evaluating various adiponectin parameters and their correlations in patients suffering from ED will be exposed. A brief summary of current knowledge on the possible biological explanation of the role played by adiponectin in ED will also be presented.
Methods A comprehensive review of the available literature via MedLine is done using the term ‘‘adiponectin’’ in association with one of the following terms: ‘‘anorexia nervosa’’, ‘‘bulimia nervosa’’, ‘‘binge eating disorder’’ or ‘‘eating disorders’’. All articles relevant to the objective of the review have been considered without any restriction related to the date of publication and the language in which the manuscript has been written.
Adiponectin in anorexia nervosa (AN) Studies evaluating serum levels of adiponectin in patients suffering from AN are summarized in Table 1. No clinical study evaluating serum adiponectin levels and other related parameters in male subjects with AN or other ED has been done until now. A majority of studies demonstrate that these levels in patients suffering from AN are higher than those found in healthy women [14–27]. These levels are also higher than those found in obese women [23, 28]. When the subtype of AN is taken into consideration both AN with restrictive subtype (R-AN) and binge/purge subtype (BP-AN) show higher serum adiponectin levels than those of healthy controls with discrepant results regarding the comparison of serum adiponectin levels between R-AN and BP-AN groups [20, 21, 29]. As a matter of fact, in the study where BP-AN group manifest higher serum adiponectin levels than those R-AN group, mean BMI levels are not statistically different between both groups suggesting that these levels are determined by restrictive eating as reflected in low weight [29]. Moreover, in the study where R-AN group manifests higher serum adiponectin levels
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than BP-AN group, mean BMI levels in R-AN are lower than those of BP-AN group [21]. Only a few studies show similar adiponectin levels in AN and healthy controls [29–35]. In some of these studies, the difference between serum adiponectin levels in groups of subjects with AN and controls is evidenced when other parameters such as body fat or BMI is controlled for [30, 33]. In addition, one of these studies demonstrates the presence of an effect of binge/purge behaviors on the variability of serum adiponectin levels (p \ 0.05) [29]. Finally, in only one study, serum adiponectin levels are found to be decreased in patients with AN as compared with healthy age-matched healthy women [36]. Serum adiponectin levels are negatively correlated to BMI and/or body fat mass according to many studies [14, 17, 18, 27, 28]. Serum adiponectin levels in patients with AN before and after weight gain are also measured in many studies. A decrease of serum adiponectin levels or a tendency towards this decrease after weight gain is demonstrated [14, 24]. One study showed no difference in serum adiponectin levels before and after weight recovery in six R-AN subjects [34]. As for the relationship between the levels of adiponectin and the disease duration, a negative correlation was found: patients with longer duration presented lower adiponectin levels [27]. The percentage of each adiponectin form to total adiponectin has also been studied: the percentage of HMW adiponectin seems to be lower in AN group when compared to a control group while the percentage of LMW adiponectin seems to be higher in the AN subjects [35]. Moreover, the index HMW adiponectin/total serum adiponectin that is closely correlated with insulin sensitivity seems to decrease with weight gain [24]. The direct correlation between insulin sensitivity and serum adiponectin levels is also studied. The majority of studies evaluating this correlation used the homeostasis model assessment of insulin resistance (HOMA-IR) for the evaluation of insulin resistance and subsequently insulin sensitivity. Serum adiponectin levels are found, in two of these studies, positively correlated with insulin sensitivity [15, 18]. No correlation between serum adiponectin levels and insulin sensitivity is demonstrated in another two studies [22, 33]. However when a comparison is done between insulin resistance in patients with AN from one side and healthy controls or these same patients after they gained weight from another side, it confirms the presence of higher insulin resistance markers in recovered patients or healthy controls [17, 24, 26]. Other parameters are found to be associated to adiponectin function in patients with AN. For example, in one study, the analysis of within-group correlations in the AN group shows that serum adiponectin level positively correlated with lipid oxidation in the baseline state (r = 0.54, p = 0.022) [22]. This could be related to other findings
17 (21.8 ± 3.4)
31 (undefined; 14.0 ± 2.5) 23 (undefined; 15.0 ± 1.2) 15 (R-AN; 14.6 ± 0.49) and 11 (BP-AN; 17.3 ± 0.25) 16 (R-AN; 14.56 ± 0.43) and 10 (BP-AN; 17.19 ± 0.26) 10 (R-AN; 15.4 ± 0.64) Group 1: 20 (R-AN; 15.9 ± 1.8) and Group 2: 18 (R-AN; 15.9 ± 0.9) 20 (R-AN; 15.3 ± 2.1) and 7 (BP-AN; 15.0 ± 1.6) 12 (R-AN; 16.37 ± 0.41) 19 (undefined; 16.7 ± 1.3) 9 (R-AN and BP-AN; 12.0 ± 0.4) and 6 partially recovered (17.2 ± 1.3) 28 (undefined; 15.72 ± 0.36)
Tagami et al. [34]
Bosy-Westphal et al. [14]
Housova et al. [20]
Housova et al. [21]
Dosta´lova´ et al. [17, 18] Modan-Moses et al. [24]
Stoving et al. [26]
Doleza´lova´ et al. [16]
Misra et al. [33]
Miljic et al. [31]
28 (R-AN; 16.8 ± 0.20) 9 (R-AN; 13.01 ± 0.23)
Terra et al. 2013 [27]
Amitani et al. [35]
9 age-matched (21.59 ± 0.43)
33 (21.8 ± 0.30)
11 (21.84 ± 0.36)
14 (20.36 ± 1.77)
24 (21.02 ± 2.11)
16 (22.9 ± 0.41)
38 age-matched (22.32 ± 0.40)
10 (17.6 ± 0.4)
24 (23.6 ± 3.7)
12 (20.9 ± 0.72) 13 (20.2 ± 2.1)
12 age-matched (21.92 ± 0.7)
14 age-matched (23.21 ± 0.96)
43 (22.3 ± 2.3)
31 age-matched (20.3 ± 1.5)
AN anorexia nervosa, BMI body mass index, R-AN restrictive-AN, BP-AN binge/purge AN
24 (R-AN and BP-AN; 13.52 ± 1.19) 12 (R-AN; 13.12 ± 0.26)
Nogueira et al. [29]
Amitani et al. [34]
19 (R-AN; 15.9 ± 0.33) 21 (R-AN; 15.56 ± 1.55)
Haluzikova et al. [19]
Karczewska-Kupczewska et al. [22]
Krı´zova´ et al. [23]
18 age-matched (22.96 ± 0.67)
23 (undefined; 16.7 ± 0.2)
Misra et al. [32]
26 (20.7 ± 2.8) 26 age-matched (22.4 ± 0.7) 21 (21.7 ± 0.8)
11 (undefined; 16.4 ± 2.6) 26 (undefined; 14.3 ± 0.4)
19 (20.2 ± 2.1)
Pannaciulli et al. [25]
21 (R-AN and BP-AN; 15.1 ± 1.9)
Iwahashi et al. [30]
Number of controls (mean BMI in kg/m2)
Delporte et al. [15]
Number of patients (subtype; mean BMI in kg/m2)
Reference
Table 1 Studies evaluating serum levels of adiponectin in patients suffering from AN
6.06 ± 1.31 vs. 7.59 ± 0.61
Nearly 28 vs. nearly 17
7.52 ± 1.18 vs. 9.32 ± 1.03
11.22 ± 6.65 vs. 11.09 ± 4.86
23.03 ± 8.70 vs. 15.75 ± 5.95
36.5 ± 4.33 vs. 19.9 ± 2.29
33.5 ± 8.5 in AN group vs. 44.2 ± 3.8 in the partially recovered group vs. 37.2 ± 4.2 in the control group 58.44 ± 7.17 vs. 33.24 ± 4.41
13.3 ± 6.1 vs. 11.9 ± 7.8 (in mg/l)
38.23 ± 5.32 vs. 24.94 ± 2.92 (in ng/ml)
13.1 ± 2.0 vs. 9.7 ± 3.9 in BP-AN (in mg/l)
14.1 ± 5.6 vs. 9.7 ± 3.9 in R-AN (in mg/l)
16 ± 5.2 vs. 10.5 ± 4.1 in group 2 (in ng/ml)
46.4 ± 5.0 vs. 28.0 ± 2.9 16.8 ± 0.8 vs. 11.9 ± 3.3 in group 1 (in ng/ml)
39.81 ± 2.39 vs. 26.01 ± 2.46 in BP-AN group
50.90 ± 5.45 vs. 26.01 ± 2.46 in R-AN group
R-AN: 57.28 ± 4.86 vs. BP-AN: 40.25 ± 2.18 vs. controls: 26.84 ± 2.40
6.7 ± 3.25 vs. 5.19 ± 1.56 (in nM)
11.0 ± 7.8 vs. 18.3 ± 9.8
12.8 ± 1.1 vs. 12.5 ± 1.7
11.8 ± 0.9 vs. 16.1 ± 0.9
30.5 ± 15.8 vs. 22.6 ± 10.9
12.2 ± 4.2 vs. 10.0 ± 3.6
Adiponectinemia in patients vs. adiponectinemia in controls (lg/ml)
Not significant
p \ 0.001
Not significant
Not significant
p \ 0.05
p \ 0.05
p \ 0.05
Not significant
Not significant
p \ 0.05
p \ 0.05 in both comparisons
p \ 0.01 p \ 0.001 in both comparisons
p \ 0.05 for both comparisons
p \ 0.05
p \ 0.05
p \ 0.01
Not significant
p \ 0.05
p \ 0.05
Not significant
p value
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Not significant 6.04 ± 3.22 vs. 5.61 ± 3.36 in lg/l BN bulimia nervosa, BED binge eating disorders
55 (BN or BED; 37.7 ± 5.29) Carnier et al. [37]
28 obese without ED (37.72 ± 5.47)
p \ 0.05
Not significant
11.5 ± 6.2 vs. 18.3 ± 9.8 16 age-matched (20.3 ± 1.5)
14 age-matched (23.21 ± 0.96)
11 (BN; 20.5 ± 1.8)
15 (BN; 21.92 ± 0.7)
Tagami et al. [34]
Number of controls (mean BMI in kg/m2)
Studies evaluating serum adiponectin levels in patients suffering from BN are summarized in Table 2. These studies show that serum adiponectin levels are higher, lower or indifferent in patients suffering from BN as compared to healthy controls [20, 36, 37]. The comparison between serum adiponectin levels of patients suffering from BN and those of patients suffering from AN shows that patients with BN have higher serum adiponectin levels [37]. Obese patients suffering from BN or binge eating disorder (BED) are shown to have equal serum adiponectin levels than those of obese subjects without BN or BED neither at baseline nor after 1 year of interdisciplinary therapy [38]. In patients suffering from BN there seems to be a positive correlation between the frequency of bingeing/vomiting and serum adiponectin levels [37]. As a matter of fact, BN patients constitute a highly heterogeneous population manifesting different bingeing/purging frequencies and presenting a higher variability in their BMI and their fat mass as compared to patients with AN. This may explain the divergence in findings emanating from the few studies that were interested in measuring serum adiponectin levels in patients with BN. Theoretically, BN individuals should manifest a serum adiponectin level that is amid between that of patients with AN and that of healthy individuals. As with the comparison between AN subtypes, a certain role appears to be played by the
Table 2 Studies evaluating serum adiponectin levels in patients suffering from BN and BED
Adiponectin in bulimia nervosa (BN)
Housova et al. [21]
20 (BN; 22.2 ± 3.5) and 20 (BED; 33.9 ± 7.0) Monteleone et al. [36]
Not clarified in text (higher than controls in BN and lower than controls in BED) 20 (21.8 ± 1.7)
Number of patients (type of ED; mean BMI in kg/m2) Reference
Adiponectinemia in patients vs. adiponectinemia in controls (lg/ml)
p value
where serum cholesterol levels in patients with AN are shown to be correlated to a specific polymorphism in adiponectin gene [23]. In a study where AN patients are compared to obese subjects, adiponectin receptor type 1 expression is found to be, in lymphocytes, twice as that of adiponectin receptor type 2 in both groups. This receptor’s expression seems positively correlated with serum adiponectin levels (p \ 0.01) and to be more important in patients with AN than in obese subjects (p \ 0.005 for adiponectin receptor type 1 and p \ 0.05 for adiponectin receptor type 2) [28]. However, this finding is not reproduced when the subcutaneous adipose tissue of patients suffering from AN is evaluated. The expression of adiponectin receptors as reflected by the level of messenger ribonucleic acid (mRNA) is markedly decreased in subcutaneous adipose tissue of AN patients relative to the control group and adiponectin receptors type 1 and 2 mRNA expression is not significantly different between both groups (p \ 0.05) [16]. Accordingly, adiponectin receptor profile in patients suffering from AN is suspected to be different in the central nervous system and more specifically in brain regions responsible in appetite regulation and food intake as compared to peripheral tissues.
29.95 ± 3.56 vs. 26.01 ± 2.46
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p \ 0.002 in the comparison with BN and p \ 0.005 in the comparison with BED
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frequency of bingeing and purging in the augmentation of serum adiponectin levels or vice versa.
Adiponectin and BED Studies evaluating serum adiponectin levels in patients suffering from BED are presented in Table 2. Based on a unique study, serum adiponectin levels appear to be lower in subjects suffering from BED than in healthy controls [37]. As previously mentioned, no difference in adiponectin levels were found between obese adolescents with BN or BED and those without any eating disorder at baseline and after 1 year of interdisciplinary therapy [38]. Patients with BED do not demonstrate a correlation between the frequency of binge eating and adiponectin levels [37]. This finding and the one concerning the correlation between the frequency of bingeing/vomiting and serum adiponectin levels point toward a possible correlation between purging behavior alone and serum adiponectin levels.
Biological correlates of adiponectin and eating disorders Control of food intake is one component of energy balance where endocrine signaling from the periphery to the central nervous system has a very important role [39]. In fact, energy homeostasis includes the regulation of nutrient levels in storage organs as well as in blood. When the brain receives continuous information about food that is being eaten and absorbed and about basal and situational energy needs by tissues, it in turn controls tissues that have important roles in energy homeostasis like the liver and musculoskeletal system as well as the secretion of key metabolically active hormones [39]. Moreover, in the human brain, the arcuate nucleus of the hypothalamus houses two opposing sets of neuronal circuitry, an appetitestimulating circuit and an appetite-inhibiting circuit. The two circuits send signals mainly to the paraventricular nucleus but also to other nuclei of the hypothalamus, which then directly modulate feeding behavior. The appetitestimulatory and appetite-inhibitory circuits are influenced by peripheral hormonal signals that are able to cross the blood–brain barrier. Neuropeptide Y, for example, stimulates the appetite-stimulatory circuit while leptin and insulin stimulate the appetite-inhibitory circuit [40]. In addition, the hormone leptin is secreted by adipocytes in proportion to body fat mass and plays a key role in energy homeostasis by informing the brain of changes in both energy balance and the amount of fuel stored as fat [41]. In fact, receptors of both insulin and leptin are widely
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expressed throughout the central nervous system and, the medial hypothalamus, a key center for the regulation of energy homeostasis and coordination of metabolic events is a major target for both insulin and leptin action [42]. Adiponectin has insulin-sensitizing function and plays an important role in maintaining energy homeostasis. In addition, the amount of energy intake is important in controlling adiponectin gene expression in white adipose tissue [43]. However, metabolic need is not the only motivation to eat food [44] and the controls of appetite are not limited to the hypothalamus but engage many other parts of the brain in particular the caudal brainstem, the senses and cortico-limbic systems, which led to the distinction between homeostatic and non-homeostatic controls of appetite and body weight regulation [45]. Eating while there is no metabolic hunger may seem incompatible with the traditional view of homeostatic energy, which should take into account the need to adapt to changing conditions in the environment [46]. Low levels of adiponectin have been found in the cerebrospinal fluid in humans showing that this adipokine may cross the blood–brain barrier [47]. In some animals, adiponectin may be locally expressed in the brain tissue [48, 49]. Adiponectin receptor types 1 and 2 are located throughout the central nervous system, notably in important regions of the hypothalamus and brainstem that control autonomic function and feeding behavior such as area postrema, the arcuate nucleus and the paraventricular nucleus [49–52]. Peripheral administration of adiponectin reduces body weight by enhancing energy expenditure and fatty acid oxidation but also possibly by reducing food intake [53–56]. Preclinical data support the fact that intracerebroventricular injection of adiponectin promotes weight loss via reduction in food intake and/or energy expenditure increase by activating the classical insulin and leptin signaling pathways through adiponectin type 1 receptor stimulation and by increasing corticotrophinreleasing hormone (CRH) known to its endogenous anorectic and thermogenic effects [52, 57, 58]. The anorectic effect of adiponectin may also be reversed due to variability in leptin concentration and action, in a cross-talk between those two adipokines maintaining an equilibrium of appetite in normal states [52]. In order to understand the biological role of adiponectin in patients with ED, one might speculatively approach the problem of ED as a unique alteration in appetite and body image manifesting through multiple phenotypic clinical manifestations. Accordingly, AN may be considered as a prototype of ED. Many factors may explain why adiponectin is elevated in patients suffering from AN such as the reduced fat mass per se since a negative feedback mechanism has been shown to regulate adipose tissue mass, the effect of increased insulin sensitivity in AN since insulin
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stimulates adiponectin gene expression, the decrease in sympathetic tone and the alteration in cytokines that regulates adiponectin expression such as TNFa and Il-6 [59]. In fact, although the expression of adiponectin is highly specific to adipose tissue, it is decreased in human obesity [60]. On the other hand, its circulating level is markedly reduced in patients with generalized lipodystrophy. In AN, similarly to lipodystrophy, an inadequate adipose tissue mass is observed, which could explain the higher level of adiponectin in patients suffering from AN [22]. However, it has been demonstrated in mice that intracerebroventricular administration of adiponectin decreased body weight. Therefore, it could be speculated that hyperadiponectinemia could contribute to the etiopathogenesis of anorexia nervosa [57]. As for TNF-a and oxidative stress, their activation was observed in patients suffering from anorexia nervosa. Besides, there is a correlation between TNF-a receptors and both BMI and disease duration which suggests a possible role of pro-inflammatory cytokines in the evolution of AN [61]. Once installed, hyperadiponectinemia perpetuates enhanced insulin sensitivity, low bone mineral density and dysregulated hematopoiesis [59]. Hyperadiponectinemia may contribute to further reduction of body weight by enhancing energy expenditure and fatty acid oxidation. Most importantly, the action of hyperadiponectinemia on the central nervous system may be crucial in appetite control and possibly in central thermoregulation. Susceptible individuals towards AN may be more sensitive to the central effect of adiponectin after an initial period of food intake restriction due, for example, to a major depressive disorder or to a self-inflicted diet. This vulnerability may speculatively be due to an overexpression of adiponectin type 1 receptors as compared to type 2 receptors in the hypothalamus as well as to a disequilibrium in adiponectin/leptin crosstalk (providing that serum leptin levels are also usually decreased in patients with AN) [25, 59]. In this perspective, patient suffering from BP-AN, BN or BED may have different adiponectin receptors expression profiles as well as different leptin concentrations and receptors profiles.
Conclusion Adiponectin is an important adipokine in the physiopathology of ED. Elevated serum levels of adiponectin are frequently found in patients suffering from AN especially when controlling for BMI and/or body fat mass. Decreased serum levels of adiponectin are found in patients suffering from BED. Discrepant results concerning serum adiponectin levels are found in patients with BN. In addition to the role of adiponectin in enhancing insulin sensitivity in patients with AN as well as in participating to the induction of some
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endocrinologic and hematopoietic complications, evidence support the fact that hyperadiponectinemia plays a central and peripheral role in food intake reduction and weight loss. Some of the determinants of adiponectin’s pathological effect might determine the phenotypic clinical presentation of the ED such as whether it is accompanied by binge/purge behaviors. However, the variations of adiponectin levels in eating disorders could be considered as an adaptive phenomenon related to the variation of body fat content. Further studies are needed in order to elucidate the exact role of adiponectin and its multimers in ED. This could theoretically help in developing novel therapeutics for ED. Conflict of interest
None.
References 1. Arita Y, Kihara S, Ouchi N et al (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83 2. Scherer PE, Williams S, Fogliano M et al (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749 3. Shapiro L, Scherer PE (1998) The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8:335–338 4. Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703 5. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451 6. Nishida M, Funahashi T, Shimomura I (2007) Pathophysiological significance of adiponectin. Med Mol Morphol 40:55–67 7. Matsubara M, Maruoka S, Katayose S (2002) Inverse relationship between plasma adiponectin and leptin concentrations in normalweight and obese women. Eur J Endocrinol 147:173–180 8. Cnop M, Havel PJ, Utzschneider KM et al (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–469 9. Lara-Castro C, Luo N, Wallace P et al (2006) Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55:249–259 10. Yamauchi T, Kamon J, Ito Y et al (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769 11. Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab 296:E22–E36 12. Lindsay RS, Funahashi T, Hanson RL et al (2002) Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360:57–58 13. Brochu-Gaudreau K, Rehfeldt C, Blouin R et al (2010) Adiponectin action from head to toe. Endocrine 37:11–32 14. Bosy-Westphal A, Brabant G, Haas V et al (2005) Determinants of plasma adiponectin levels in patients with anorexia nervosa examined before and after weight gain. Eur J Nutr 44:355–359 15. Delporte ML, Brichard SM, Hermans MP et al (2003) Hyperadiponectinaemia in anorexia nervosa. Clin Endocrinol (Oxf) 58:22–29 16. Dolezalova R, Lacinova Z, Dolinkova M et al (2007) Changes of endocrine function of adipose tissue in anorexia nervosa:
Eat Weight Disord (2014) 19:3–10
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
comparison of circulating levels versus subcutaneous mRNA expression. Clin Endocrinol (Oxf) 67:674–678 Dosta´lova´ I, Smitka K, Papezova´ H et al (2006) The role of adiponectin in increased insulin sensitivity of patients with anorexia nervosa. Vnitr Lek 52:887–890 Dosta´lova´ I, Smitka K, Papezova´ H et al (2007) Increased insulin sensitivity in patients with anorexia nervosa: the role of adipocytokines. Physiol Res 56:587–594 Haluzı´kova´ D, Dosta´lova´ I, Kava´lkova´ P et al (2009) Serum concentrations of adipocyte fatty acid binding protein in patients with anorexia nervosa. Physiol Res 58:577–581 Housova J, Anderlova K, Krizova´ J et al (2005) Serum adiponectin and resistin concentrations in patients with restrictive and binge/purge form of anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 90:1366–1370 Housova´ J, Kiziova´ J, Anderlova K et al (2005) Serum concentrations of adiponectin in patients with restrictive and purgative subtype of mental anorexia. Cas Lek Cesk 144:278–281 Karczewska-Kupczewska M, Straczkowski M, Adamska A et al (2010) Insulin sensitivity, metabolic flexibility, and serum adiponectin concentration in women with anorexia nervosa. Metabolism 59:473–477 Krı´zova´ J, Dolinkova´ M, Lacinova´ Z et al (2008) Adiponectin and resistin gene polymorphisms in patients with anorexia nervosa and obesity and its influence on metabolic phenotype. Physiol Res 57:539–546 Modan-Moses D, Stein D, Pariente C et al (2007) Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J Clin Endocrinol Metab 92:1843–1847 Pannacciulli N, Vettor R, Milan G et al (2003) Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 88:1748–1752 Støving RK, Chen JW, Glintborg D et al (2007) Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa. J Clin Endocrinol Metab 92:2323–2329 Terra X, Auguet T, Aguera Z et al (2013) Adipocytokine levels in women with anorexia nervosa. Relationship with weight restoration and disease duration. Int J Eat Disord. doi:10.1002/eat. 22166 Alberti L, Gilardini L, Girola A et al (2007) Adiponectin receptors gene expression in lymphocytes of obese and anorexic patients. Diabetes Obes Metab 9:344–349 Nogueira JP, Maraninchi M, Lorec AM et al (2010) Specific adipocytokines profiles in patients with hyperactive and/or binge/ purge form of anorexia nervosa. Eur J Clin Nutr 64:840–844 Iwahashi H, Funahashi T, Kurokawa N et al (2003) Plasma adiponectin levels in women with anorexia nervosa. Horm Metab Res 35:537–540 Miljic D, Djurovic M, Pekic S et al (2007) Glucose metabolism during ghrelin infusion in patients with anorexia nervosa. J Endocrinol Invest 30:771–775 Misra M, Miller KK, Almazan C et al (2004) Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. J Clin Endocrinol Metab 89:3486–3495 Misra M, Miller KK, Cord J et al (2007) Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab 92:2046–2052 Amitani M, Asakawa A, Amitani H et al (2013) Plasma klotho levels decrease in both anorexia nervosa and obesity. Nutrition 29(9):1106–1109 Amitani H, Asakawa A, Ogiso K et al (2013) The role of adiponectin multimers in anorexia nervosa. Nutrition 29(1):203–206
9 36. Tagami T, Satoh N, Usui T et al (2004) Adiponectin in anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 89:1833–1837 37. Monteleone P, Fabrazzo M, Martiadis V et al (2003) Opposite changes in circulating adiponectin in women with bulimia nervosa or binge eating disorder. J Clin Endocrinol Metab 88:5387–5391 38. Carnier J, Sanches PD, da Silva PL et al (2011) Obese adolescents with eating disorders: analysis of metabolic and inflammatory states. Physiol Behav 105:175–180 39. Woods S, D’Alessio D (2008) Central control of body weight and appetite. J Clin Endocrinol Metab 93(11 (Suppl 1)):S37–S50 40. Gale SM, Castracane VD, Mantzoros CS (2004) Energy homeostasis, obesity and eating disorders: recent advances in endocrinology. J Nutr 134:295–298 41. Guyenet S, Schwartz M (2012) Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 97(3):745–755 42. Figlewicz D, Sipols A (2010) Energy regulatory signals and food reward. Pharmacol Biochem Behav 97(1):15–24 43. Qiao L, Lee B, Kinney B, Yoo H, Shao J (2011) Energy intake and adiponectin gene expression. Am J Physiol Endocrinol Metab 300(5):E809–E816 44. Faulconbridge L, Hayes M (2011) Regulation of energy balance and body weight by the brain: a distributed system prone to disruption. Psychiatr Clin North Am 34(4):733–745 45. Corwin RL, Hajnal A (2005) Too much of a good thing: neurobiology of non-homeostatic eating and drug abuse. Physiol Behav 86(1–2):5–8 46. Shin A, Zheng H, Berthoud H (2009) An expanded view of energy homeostasis: neural integration of metabolic, cognitive, and emotional drives to eat. Physiol Behav 97(5):572–580 47. Kos K, Harte AL, da Silva NF et al (2007) Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J Clin Endocrinol Metab 92:1129–1136 48. Maddineni S, Metzger S, Oco´n O et al (2005) Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology 146:4250–4256 49. Wilkinson M, Brown R, Imran SA et al (2007) Adipokine gene expression in brain and pituitary gland. Neuroendocrinology 86:191–209 50. Fry M, Smith PM, Hoyda TD et al (2006) Area postrema neurons are modulated by the adipocyte hormone adiponectin. J Neurosci 26:9695–9702 51. Guillod-Maximin E, Roy AF, Vacher CM et al (2009) Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons. J Endocrinol 200:93–105 52. Kubota N, Yano W, Kubota T et al (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6:55–68 53. Berg AH, Combs TP, Du X et al (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953 54. Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946 55. Shklyaev S, Aslanidi G, Tennant M et al (2003) Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci USA 100:14217–14222 56. Tomas E, Tsao TS, Saha AK et al (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313
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10 57. Qi Y, Takahashi N, Hileman SM et al (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10:524–529 58. Coope A, Milanski M, Arau´jo EP et al (2008) AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus. FEBS Lett 582:1471–1476 59. Brichard SM, Delporte ML, Lambert M (2003) Adipocytokines in anorexia nervosa: a review focusing on leptin and adiponectin. Horm Metab Res 35:337–342
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Eat Weight Disord (2014) 19:3–10 60. Kern PA, Di Gregorio GB, Lu T et al (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52(7):1779–1785 61. Agnello E, Malfi G, Costantino AM (2012) Tumour necrosis factor alpha and oxidative stress as maintaining factors in the evolution of anorexia nervosa. Eat Weight Disord 17(3):e194–e199
REVIEW
Adiponectin in eating disorders Rami Bou Khalil • Charline El Hachem
Received: 9 September 2013 / Accepted: 19 December 2013 / Published online: 28 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Purpose To elucidate the possible role of adiponectin, an adipokine secreted by white adipose tissue that plays an important role in the neuromodulation of food intake, in the pathogenesis of eating disorders. Methods A comprehensive review of the available literature via MedLine is done using the term ‘‘adiponectin’’ in association with one of the following terms: ‘‘anorexia nervosa’’, ‘‘bulimia nervosa’’, ‘‘binge eating disorder’’ or ‘‘eating disorders’’. Results The majority of studies evaluating serum adiponectin levels in patients with eating disorders show that serum adiponectin levels are increased in patients with anorexia nervosa. After refeeding, adiponectin levels tend to rejoin the levels of healthy individuals. Data concerning serum adiponectin levels in patients with bulimia nervosa show that these levels can be equal, higher or lower than those found in healthy controls and lower than those found in anorexia nervosa patients. Binge eating disorder is accompanied with lower serum adiponectin levels than normal. Adiponectin receptor type 1 seems to be more related to the central pathological effect of adiponectin on eating behavior. Conclusion The potential role that plays adiponectin in the pathogenesis of eating disorders needs to be elucidated by further studies.
R. Bou Khalil (&) C. El Hachem Saint Joseph University, Beirut, Lebanon e-mail: [email protected] R. Bou Khalil Psychiatric Hospital of the Cross, P.O. box: 60096, Jalledib, Lebanon
Keywords Adiponectin Eating disorders Anorexia nervosa Bulimia nervosa Binge eating disorders
Introduction Adiponectin is a 30-kDa protein mainly secreted by the adipose tissue and reaches a plasma concentration of 2–10 lg/ml in humans [1]. It is a 244-amino-acid protein composed of an amino-terminal signal peptide followed by a species-specific variable domain, a collagenous domain of 22 Gly-X–Y repeats, and a carboxyl-terminal globular domain that is similar to the complement factor C1q and structurally similar to tumor necrosis factor-a (TNFa) [2– 4]. In the blood circulation, adiponectin exists as multiple isoforms: a low-molecular-weight (LMW) form, a middlemolecular-weight (MMW) form, and a high-molecularweight (HMW) form [5]. Although adiponectin is secreted mainly by white adipose tissue, its expression was also found, in humans, in salivary gland epithelial cells, bone marrow, osteoblasts, fetal tissue, myocytes and cardiomyocytes [6]. The serum concentrations of adiponectin, unlike most of the other adipokines, are inversely correlated with body mass index (BMI) and visceral fat accumulation [7–9]. Three adiponectin receptors have been identified: adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) and, more recently, T-cadherin [10]. Adiponectin primarily mediates its insulin-sensitizing effects through the sequential activation of adenosine monophosphate-activated protein kinase (AMPK), p38 mitogenactivated protein kinase (MAPK) and peroxisome proliferator activated receptor-alpha (PPARa) [11]. Accumulating evidence suggests that adipose-tissue derived hormones such as adiponectin may act as key neuromodulators of food intake, energy expenditure and reproductive
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functions. Individuals with high concentrations of this protein are less likely to develop type 2 diabetes than those with low concentrations, thus supporting the hypothesis that adiponectin may play a role in the progression from obesity to type 2 diabetes [12]. There is a disagreement about the exact role of adiponectin in the brain. However, the wide distribution of adiponectin receptors, the local production of adiponectin, and the release of somatotrophs and gonadotrophs from rat pituitary cell cultures strengthen the hypothesis that adiponectin has a real effect in the brain [13]. In this article the role of adiponectin in eating disorders (ED) will be reviewed. Clinical studies evaluating various adiponectin parameters and their correlations in patients suffering from ED will be exposed. A brief summary of current knowledge on the possible biological explanation of the role played by adiponectin in ED will also be presented.
Methods A comprehensive review of the available literature via MedLine is done using the term ‘‘adiponectin’’ in association with one of the following terms: ‘‘anorexia nervosa’’, ‘‘bulimia nervosa’’, ‘‘binge eating disorder’’ or ‘‘eating disorders’’. All articles relevant to the objective of the review have been considered without any restriction related to the date of publication and the language in which the manuscript has been written.
Adiponectin in anorexia nervosa (AN) Studies evaluating serum levels of adiponectin in patients suffering from AN are summarized in Table 1. No clinical study evaluating serum adiponectin levels and other related parameters in male subjects with AN or other ED has been done until now. A majority of studies demonstrate that these levels in patients suffering from AN are higher than those found in healthy women [14–27]. These levels are also higher than those found in obese women [23, 28]. When the subtype of AN is taken into consideration both AN with restrictive subtype (R-AN) and binge/purge subtype (BP-AN) show higher serum adiponectin levels than those of healthy controls with discrepant results regarding the comparison of serum adiponectin levels between R-AN and BP-AN groups [20, 21, 29]. As a matter of fact, in the study where BP-AN group manifest higher serum adiponectin levels than those R-AN group, mean BMI levels are not statistically different between both groups suggesting that these levels are determined by restrictive eating as reflected in low weight [29]. Moreover, in the study where R-AN group manifests higher serum adiponectin levels
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than BP-AN group, mean BMI levels in R-AN are lower than those of BP-AN group [21]. Only a few studies show similar adiponectin levels in AN and healthy controls [29–35]. In some of these studies, the difference between serum adiponectin levels in groups of subjects with AN and controls is evidenced when other parameters such as body fat or BMI is controlled for [30, 33]. In addition, one of these studies demonstrates the presence of an effect of binge/purge behaviors on the variability of serum adiponectin levels (p \ 0.05) [29]. Finally, in only one study, serum adiponectin levels are found to be decreased in patients with AN as compared with healthy age-matched healthy women [36]. Serum adiponectin levels are negatively correlated to BMI and/or body fat mass according to many studies [14, 17, 18, 27, 28]. Serum adiponectin levels in patients with AN before and after weight gain are also measured in many studies. A decrease of serum adiponectin levels or a tendency towards this decrease after weight gain is demonstrated [14, 24]. One study showed no difference in serum adiponectin levels before and after weight recovery in six R-AN subjects [34]. As for the relationship between the levels of adiponectin and the disease duration, a negative correlation was found: patients with longer duration presented lower adiponectin levels [27]. The percentage of each adiponectin form to total adiponectin has also been studied: the percentage of HMW adiponectin seems to be lower in AN group when compared to a control group while the percentage of LMW adiponectin seems to be higher in the AN subjects [35]. Moreover, the index HMW adiponectin/total serum adiponectin that is closely correlated with insulin sensitivity seems to decrease with weight gain [24]. The direct correlation between insulin sensitivity and serum adiponectin levels is also studied. The majority of studies evaluating this correlation used the homeostasis model assessment of insulin resistance (HOMA-IR) for the evaluation of insulin resistance and subsequently insulin sensitivity. Serum adiponectin levels are found, in two of these studies, positively correlated with insulin sensitivity [15, 18]. No correlation between serum adiponectin levels and insulin sensitivity is demonstrated in another two studies [22, 33]. However when a comparison is done between insulin resistance in patients with AN from one side and healthy controls or these same patients after they gained weight from another side, it confirms the presence of higher insulin resistance markers in recovered patients or healthy controls [17, 24, 26]. Other parameters are found to be associated to adiponectin function in patients with AN. For example, in one study, the analysis of within-group correlations in the AN group shows that serum adiponectin level positively correlated with lipid oxidation in the baseline state (r = 0.54, p = 0.022) [22]. This could be related to other findings
17 (21.8 ± 3.4)
31 (undefined; 14.0 ± 2.5) 23 (undefined; 15.0 ± 1.2) 15 (R-AN; 14.6 ± 0.49) and 11 (BP-AN; 17.3 ± 0.25) 16 (R-AN; 14.56 ± 0.43) and 10 (BP-AN; 17.19 ± 0.26) 10 (R-AN; 15.4 ± 0.64) Group 1: 20 (R-AN; 15.9 ± 1.8) and Group 2: 18 (R-AN; 15.9 ± 0.9) 20 (R-AN; 15.3 ± 2.1) and 7 (BP-AN; 15.0 ± 1.6) 12 (R-AN; 16.37 ± 0.41) 19 (undefined; 16.7 ± 1.3) 9 (R-AN and BP-AN; 12.0 ± 0.4) and 6 partially recovered (17.2 ± 1.3) 28 (undefined; 15.72 ± 0.36)
Tagami et al. [34]
Bosy-Westphal et al. [14]
Housova et al. [20]
Housova et al. [21]
Dosta´lova´ et al. [17, 18] Modan-Moses et al. [24]
Stoving et al. [26]
Doleza´lova´ et al. [16]
Misra et al. [33]
Miljic et al. [31]
28 (R-AN; 16.8 ± 0.20) 9 (R-AN; 13.01 ± 0.23)
Terra et al. 2013 [27]
Amitani et al. [35]
9 age-matched (21.59 ± 0.43)
33 (21.8 ± 0.30)
11 (21.84 ± 0.36)
14 (20.36 ± 1.77)
24 (21.02 ± 2.11)
16 (22.9 ± 0.41)
38 age-matched (22.32 ± 0.40)
10 (17.6 ± 0.4)
24 (23.6 ± 3.7)
12 (20.9 ± 0.72) 13 (20.2 ± 2.1)
12 age-matched (21.92 ± 0.7)
14 age-matched (23.21 ± 0.96)
43 (22.3 ± 2.3)
31 age-matched (20.3 ± 1.5)
AN anorexia nervosa, BMI body mass index, R-AN restrictive-AN, BP-AN binge/purge AN
24 (R-AN and BP-AN; 13.52 ± 1.19) 12 (R-AN; 13.12 ± 0.26)
Nogueira et al. [29]
Amitani et al. [34]
19 (R-AN; 15.9 ± 0.33) 21 (R-AN; 15.56 ± 1.55)
Haluzikova et al. [19]
Karczewska-Kupczewska et al. [22]
Krı´zova´ et al. [23]
18 age-matched (22.96 ± 0.67)
23 (undefined; 16.7 ± 0.2)
Misra et al. [32]
26 (20.7 ± 2.8) 26 age-matched (22.4 ± 0.7) 21 (21.7 ± 0.8)
11 (undefined; 16.4 ± 2.6) 26 (undefined; 14.3 ± 0.4)
19 (20.2 ± 2.1)
Pannaciulli et al. [25]
21 (R-AN and BP-AN; 15.1 ± 1.9)
Iwahashi et al. [30]
Number of controls (mean BMI in kg/m2)
Delporte et al. [15]
Number of patients (subtype; mean BMI in kg/m2)
Reference
Table 1 Studies evaluating serum levels of adiponectin in patients suffering from AN
6.06 ± 1.31 vs. 7.59 ± 0.61
Nearly 28 vs. nearly 17
7.52 ± 1.18 vs. 9.32 ± 1.03
11.22 ± 6.65 vs. 11.09 ± 4.86
23.03 ± 8.70 vs. 15.75 ± 5.95
36.5 ± 4.33 vs. 19.9 ± 2.29
33.5 ± 8.5 in AN group vs. 44.2 ± 3.8 in the partially recovered group vs. 37.2 ± 4.2 in the control group 58.44 ± 7.17 vs. 33.24 ± 4.41
13.3 ± 6.1 vs. 11.9 ± 7.8 (in mg/l)
38.23 ± 5.32 vs. 24.94 ± 2.92 (in ng/ml)
13.1 ± 2.0 vs. 9.7 ± 3.9 in BP-AN (in mg/l)
14.1 ± 5.6 vs. 9.7 ± 3.9 in R-AN (in mg/l)
16 ± 5.2 vs. 10.5 ± 4.1 in group 2 (in ng/ml)
46.4 ± 5.0 vs. 28.0 ± 2.9 16.8 ± 0.8 vs. 11.9 ± 3.3 in group 1 (in ng/ml)
39.81 ± 2.39 vs. 26.01 ± 2.46 in BP-AN group
50.90 ± 5.45 vs. 26.01 ± 2.46 in R-AN group
R-AN: 57.28 ± 4.86 vs. BP-AN: 40.25 ± 2.18 vs. controls: 26.84 ± 2.40
6.7 ± 3.25 vs. 5.19 ± 1.56 (in nM)
11.0 ± 7.8 vs. 18.3 ± 9.8
12.8 ± 1.1 vs. 12.5 ± 1.7
11.8 ± 0.9 vs. 16.1 ± 0.9
30.5 ± 15.8 vs. 22.6 ± 10.9
12.2 ± 4.2 vs. 10.0 ± 3.6
Adiponectinemia in patients vs. adiponectinemia in controls (lg/ml)
Not significant
p \ 0.001
Not significant
Not significant
p \ 0.05
p \ 0.05
p \ 0.05
Not significant
Not significant
p \ 0.05
p \ 0.05 in both comparisons
p \ 0.01 p \ 0.001 in both comparisons
p \ 0.05 for both comparisons
p \ 0.05
p \ 0.05
p \ 0.01
Not significant
p \ 0.05
p \ 0.05
Not significant
p value
Eat Weight Disord (2014) 19:3–10 5
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Not significant 6.04 ± 3.22 vs. 5.61 ± 3.36 in lg/l BN bulimia nervosa, BED binge eating disorders
55 (BN or BED; 37.7 ± 5.29) Carnier et al. [37]
28 obese without ED (37.72 ± 5.47)
p \ 0.05
Not significant
11.5 ± 6.2 vs. 18.3 ± 9.8 16 age-matched (20.3 ± 1.5)
14 age-matched (23.21 ± 0.96)
11 (BN; 20.5 ± 1.8)
15 (BN; 21.92 ± 0.7)
Tagami et al. [34]
Number of controls (mean BMI in kg/m2)
Studies evaluating serum adiponectin levels in patients suffering from BN are summarized in Table 2. These studies show that serum adiponectin levels are higher, lower or indifferent in patients suffering from BN as compared to healthy controls [20, 36, 37]. The comparison between serum adiponectin levels of patients suffering from BN and those of patients suffering from AN shows that patients with BN have higher serum adiponectin levels [37]. Obese patients suffering from BN or binge eating disorder (BED) are shown to have equal serum adiponectin levels than those of obese subjects without BN or BED neither at baseline nor after 1 year of interdisciplinary therapy [38]. In patients suffering from BN there seems to be a positive correlation between the frequency of bingeing/vomiting and serum adiponectin levels [37]. As a matter of fact, BN patients constitute a highly heterogeneous population manifesting different bingeing/purging frequencies and presenting a higher variability in their BMI and their fat mass as compared to patients with AN. This may explain the divergence in findings emanating from the few studies that were interested in measuring serum adiponectin levels in patients with BN. Theoretically, BN individuals should manifest a serum adiponectin level that is amid between that of patients with AN and that of healthy individuals. As with the comparison between AN subtypes, a certain role appears to be played by the
Table 2 Studies evaluating serum adiponectin levels in patients suffering from BN and BED
Adiponectin in bulimia nervosa (BN)
Housova et al. [21]
20 (BN; 22.2 ± 3.5) and 20 (BED; 33.9 ± 7.0) Monteleone et al. [36]
Not clarified in text (higher than controls in BN and lower than controls in BED) 20 (21.8 ± 1.7)
Number of patients (type of ED; mean BMI in kg/m2) Reference
Adiponectinemia in patients vs. adiponectinemia in controls (lg/ml)
p value
where serum cholesterol levels in patients with AN are shown to be correlated to a specific polymorphism in adiponectin gene [23]. In a study where AN patients are compared to obese subjects, adiponectin receptor type 1 expression is found to be, in lymphocytes, twice as that of adiponectin receptor type 2 in both groups. This receptor’s expression seems positively correlated with serum adiponectin levels (p \ 0.01) and to be more important in patients with AN than in obese subjects (p \ 0.005 for adiponectin receptor type 1 and p \ 0.05 for adiponectin receptor type 2) [28]. However, this finding is not reproduced when the subcutaneous adipose tissue of patients suffering from AN is evaluated. The expression of adiponectin receptors as reflected by the level of messenger ribonucleic acid (mRNA) is markedly decreased in subcutaneous adipose tissue of AN patients relative to the control group and adiponectin receptors type 1 and 2 mRNA expression is not significantly different between both groups (p \ 0.05) [16]. Accordingly, adiponectin receptor profile in patients suffering from AN is suspected to be different in the central nervous system and more specifically in brain regions responsible in appetite regulation and food intake as compared to peripheral tissues.
29.95 ± 3.56 vs. 26.01 ± 2.46
Eat Weight Disord (2014) 19:3–10
p \ 0.002 in the comparison with BN and p \ 0.005 in the comparison with BED
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frequency of bingeing and purging in the augmentation of serum adiponectin levels or vice versa.
Adiponectin and BED Studies evaluating serum adiponectin levels in patients suffering from BED are presented in Table 2. Based on a unique study, serum adiponectin levels appear to be lower in subjects suffering from BED than in healthy controls [37]. As previously mentioned, no difference in adiponectin levels were found between obese adolescents with BN or BED and those without any eating disorder at baseline and after 1 year of interdisciplinary therapy [38]. Patients with BED do not demonstrate a correlation between the frequency of binge eating and adiponectin levels [37]. This finding and the one concerning the correlation between the frequency of bingeing/vomiting and serum adiponectin levels point toward a possible correlation between purging behavior alone and serum adiponectin levels.
Biological correlates of adiponectin and eating disorders Control of food intake is one component of energy balance where endocrine signaling from the periphery to the central nervous system has a very important role [39]. In fact, energy homeostasis includes the regulation of nutrient levels in storage organs as well as in blood. When the brain receives continuous information about food that is being eaten and absorbed and about basal and situational energy needs by tissues, it in turn controls tissues that have important roles in energy homeostasis like the liver and musculoskeletal system as well as the secretion of key metabolically active hormones [39]. Moreover, in the human brain, the arcuate nucleus of the hypothalamus houses two opposing sets of neuronal circuitry, an appetitestimulating circuit and an appetite-inhibiting circuit. The two circuits send signals mainly to the paraventricular nucleus but also to other nuclei of the hypothalamus, which then directly modulate feeding behavior. The appetitestimulatory and appetite-inhibitory circuits are influenced by peripheral hormonal signals that are able to cross the blood–brain barrier. Neuropeptide Y, for example, stimulates the appetite-stimulatory circuit while leptin and insulin stimulate the appetite-inhibitory circuit [40]. In addition, the hormone leptin is secreted by adipocytes in proportion to body fat mass and plays a key role in energy homeostasis by informing the brain of changes in both energy balance and the amount of fuel stored as fat [41]. In fact, receptors of both insulin and leptin are widely
7
expressed throughout the central nervous system and, the medial hypothalamus, a key center for the regulation of energy homeostasis and coordination of metabolic events is a major target for both insulin and leptin action [42]. Adiponectin has insulin-sensitizing function and plays an important role in maintaining energy homeostasis. In addition, the amount of energy intake is important in controlling adiponectin gene expression in white adipose tissue [43]. However, metabolic need is not the only motivation to eat food [44] and the controls of appetite are not limited to the hypothalamus but engage many other parts of the brain in particular the caudal brainstem, the senses and cortico-limbic systems, which led to the distinction between homeostatic and non-homeostatic controls of appetite and body weight regulation [45]. Eating while there is no metabolic hunger may seem incompatible with the traditional view of homeostatic energy, which should take into account the need to adapt to changing conditions in the environment [46]. Low levels of adiponectin have been found in the cerebrospinal fluid in humans showing that this adipokine may cross the blood–brain barrier [47]. In some animals, adiponectin may be locally expressed in the brain tissue [48, 49]. Adiponectin receptor types 1 and 2 are located throughout the central nervous system, notably in important regions of the hypothalamus and brainstem that control autonomic function and feeding behavior such as area postrema, the arcuate nucleus and the paraventricular nucleus [49–52]. Peripheral administration of adiponectin reduces body weight by enhancing energy expenditure and fatty acid oxidation but also possibly by reducing food intake [53–56]. Preclinical data support the fact that intracerebroventricular injection of adiponectin promotes weight loss via reduction in food intake and/or energy expenditure increase by activating the classical insulin and leptin signaling pathways through adiponectin type 1 receptor stimulation and by increasing corticotrophinreleasing hormone (CRH) known to its endogenous anorectic and thermogenic effects [52, 57, 58]. The anorectic effect of adiponectin may also be reversed due to variability in leptin concentration and action, in a cross-talk between those two adipokines maintaining an equilibrium of appetite in normal states [52]. In order to understand the biological role of adiponectin in patients with ED, one might speculatively approach the problem of ED as a unique alteration in appetite and body image manifesting through multiple phenotypic clinical manifestations. Accordingly, AN may be considered as a prototype of ED. Many factors may explain why adiponectin is elevated in patients suffering from AN such as the reduced fat mass per se since a negative feedback mechanism has been shown to regulate adipose tissue mass, the effect of increased insulin sensitivity in AN since insulin
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stimulates adiponectin gene expression, the decrease in sympathetic tone and the alteration in cytokines that regulates adiponectin expression such as TNFa and Il-6 [59]. In fact, although the expression of adiponectin is highly specific to adipose tissue, it is decreased in human obesity [60]. On the other hand, its circulating level is markedly reduced in patients with generalized lipodystrophy. In AN, similarly to lipodystrophy, an inadequate adipose tissue mass is observed, which could explain the higher level of adiponectin in patients suffering from AN [22]. However, it has been demonstrated in mice that intracerebroventricular administration of adiponectin decreased body weight. Therefore, it could be speculated that hyperadiponectinemia could contribute to the etiopathogenesis of anorexia nervosa [57]. As for TNF-a and oxidative stress, their activation was observed in patients suffering from anorexia nervosa. Besides, there is a correlation between TNF-a receptors and both BMI and disease duration which suggests a possible role of pro-inflammatory cytokines in the evolution of AN [61]. Once installed, hyperadiponectinemia perpetuates enhanced insulin sensitivity, low bone mineral density and dysregulated hematopoiesis [59]. Hyperadiponectinemia may contribute to further reduction of body weight by enhancing energy expenditure and fatty acid oxidation. Most importantly, the action of hyperadiponectinemia on the central nervous system may be crucial in appetite control and possibly in central thermoregulation. Susceptible individuals towards AN may be more sensitive to the central effect of adiponectin after an initial period of food intake restriction due, for example, to a major depressive disorder or to a self-inflicted diet. This vulnerability may speculatively be due to an overexpression of adiponectin type 1 receptors as compared to type 2 receptors in the hypothalamus as well as to a disequilibrium in adiponectin/leptin crosstalk (providing that serum leptin levels are also usually decreased in patients with AN) [25, 59]. In this perspective, patient suffering from BP-AN, BN or BED may have different adiponectin receptors expression profiles as well as different leptin concentrations and receptors profiles.
Conclusion Adiponectin is an important adipokine in the physiopathology of ED. Elevated serum levels of adiponectin are frequently found in patients suffering from AN especially when controlling for BMI and/or body fat mass. Decreased serum levels of adiponectin are found in patients suffering from BED. Discrepant results concerning serum adiponectin levels are found in patients with BN. In addition to the role of adiponectin in enhancing insulin sensitivity in patients with AN as well as in participating to the induction of some
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endocrinologic and hematopoietic complications, evidence support the fact that hyperadiponectinemia plays a central and peripheral role in food intake reduction and weight loss. Some of the determinants of adiponectin’s pathological effect might determine the phenotypic clinical presentation of the ED such as whether it is accompanied by binge/purge behaviors. However, the variations of adiponectin levels in eating disorders could be considered as an adaptive phenomenon related to the variation of body fat content. Further studies are needed in order to elucidate the exact role of adiponectin and its multimers in ED. This could theoretically help in developing novel therapeutics for ED. Conflict of interest
None.
References 1. Arita Y, Kihara S, Ouchi N et al (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83 2. Scherer PE, Williams S, Fogliano M et al (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749 3. Shapiro L, Scherer PE (1998) The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8:335–338 4. Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271:10697–10703 5. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451 6. Nishida M, Funahashi T, Shimomura I (2007) Pathophysiological significance of adiponectin. Med Mol Morphol 40:55–67 7. Matsubara M, Maruoka S, Katayose S (2002) Inverse relationship between plasma adiponectin and leptin concentrations in normalweight and obese women. Eur J Endocrinol 147:173–180 8. Cnop M, Havel PJ, Utzschneider KM et al (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–469 9. Lara-Castro C, Luo N, Wallace P et al (2006) Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55:249–259 10. Yamauchi T, Kamon J, Ito Y et al (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769 11. Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab 296:E22–E36 12. Lindsay RS, Funahashi T, Hanson RL et al (2002) Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360:57–58 13. Brochu-Gaudreau K, Rehfeldt C, Blouin R et al (2010) Adiponectin action from head to toe. Endocrine 37:11–32 14. Bosy-Westphal A, Brabant G, Haas V et al (2005) Determinants of plasma adiponectin levels in patients with anorexia nervosa examined before and after weight gain. Eur J Nutr 44:355–359 15. Delporte ML, Brichard SM, Hermans MP et al (2003) Hyperadiponectinaemia in anorexia nervosa. Clin Endocrinol (Oxf) 58:22–29 16. Dolezalova R, Lacinova Z, Dolinkova M et al (2007) Changes of endocrine function of adipose tissue in anorexia nervosa:
Eat Weight Disord (2014) 19:3–10
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
comparison of circulating levels versus subcutaneous mRNA expression. Clin Endocrinol (Oxf) 67:674–678 Dosta´lova´ I, Smitka K, Papezova´ H et al (2006) The role of adiponectin in increased insulin sensitivity of patients with anorexia nervosa. Vnitr Lek 52:887–890 Dosta´lova´ I, Smitka K, Papezova´ H et al (2007) Increased insulin sensitivity in patients with anorexia nervosa: the role of adipocytokines. Physiol Res 56:587–594 Haluzı´kova´ D, Dosta´lova´ I, Kava´lkova´ P et al (2009) Serum concentrations of adipocyte fatty acid binding protein in patients with anorexia nervosa. Physiol Res 58:577–581 Housova J, Anderlova K, Krizova´ J et al (2005) Serum adiponectin and resistin concentrations in patients with restrictive and binge/purge form of anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 90:1366–1370 Housova´ J, Kiziova´ J, Anderlova K et al (2005) Serum concentrations of adiponectin in patients with restrictive and purgative subtype of mental anorexia. Cas Lek Cesk 144:278–281 Karczewska-Kupczewska M, Straczkowski M, Adamska A et al (2010) Insulin sensitivity, metabolic flexibility, and serum adiponectin concentration in women with anorexia nervosa. Metabolism 59:473–477 Krı´zova´ J, Dolinkova´ M, Lacinova´ Z et al (2008) Adiponectin and resistin gene polymorphisms in patients with anorexia nervosa and obesity and its influence on metabolic phenotype. Physiol Res 57:539–546 Modan-Moses D, Stein D, Pariente C et al (2007) Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J Clin Endocrinol Metab 92:1843–1847 Pannacciulli N, Vettor R, Milan G et al (2003) Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 88:1748–1752 Støving RK, Chen JW, Glintborg D et al (2007) Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa. J Clin Endocrinol Metab 92:2323–2329 Terra X, Auguet T, Aguera Z et al (2013) Adipocytokine levels in women with anorexia nervosa. Relationship with weight restoration and disease duration. Int J Eat Disord. doi:10.1002/eat. 22166 Alberti L, Gilardini L, Girola A et al (2007) Adiponectin receptors gene expression in lymphocytes of obese and anorexic patients. Diabetes Obes Metab 9:344–349 Nogueira JP, Maraninchi M, Lorec AM et al (2010) Specific adipocytokines profiles in patients with hyperactive and/or binge/ purge form of anorexia nervosa. Eur J Clin Nutr 64:840–844 Iwahashi H, Funahashi T, Kurokawa N et al (2003) Plasma adiponectin levels in women with anorexia nervosa. Horm Metab Res 35:537–540 Miljic D, Djurovic M, Pekic S et al (2007) Glucose metabolism during ghrelin infusion in patients with anorexia nervosa. J Endocrinol Invest 30:771–775 Misra M, Miller KK, Almazan C et al (2004) Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. J Clin Endocrinol Metab 89:3486–3495 Misra M, Miller KK, Cord J et al (2007) Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab 92:2046–2052 Amitani M, Asakawa A, Amitani H et al (2013) Plasma klotho levels decrease in both anorexia nervosa and obesity. Nutrition 29(9):1106–1109 Amitani H, Asakawa A, Ogiso K et al (2013) The role of adiponectin multimers in anorexia nervosa. Nutrition 29(1):203–206
9 36. Tagami T, Satoh N, Usui T et al (2004) Adiponectin in anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab 89:1833–1837 37. Monteleone P, Fabrazzo M, Martiadis V et al (2003) Opposite changes in circulating adiponectin in women with bulimia nervosa or binge eating disorder. J Clin Endocrinol Metab 88:5387–5391 38. Carnier J, Sanches PD, da Silva PL et al (2011) Obese adolescents with eating disorders: analysis of metabolic and inflammatory states. Physiol Behav 105:175–180 39. Woods S, D’Alessio D (2008) Central control of body weight and appetite. J Clin Endocrinol Metab 93(11 (Suppl 1)):S37–S50 40. Gale SM, Castracane VD, Mantzoros CS (2004) Energy homeostasis, obesity and eating disorders: recent advances in endocrinology. J Nutr 134:295–298 41. Guyenet S, Schwartz M (2012) Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 97(3):745–755 42. Figlewicz D, Sipols A (2010) Energy regulatory signals and food reward. Pharmacol Biochem Behav 97(1):15–24 43. Qiao L, Lee B, Kinney B, Yoo H, Shao J (2011) Energy intake and adiponectin gene expression. Am J Physiol Endocrinol Metab 300(5):E809–E816 44. Faulconbridge L, Hayes M (2011) Regulation of energy balance and body weight by the brain: a distributed system prone to disruption. Psychiatr Clin North Am 34(4):733–745 45. Corwin RL, Hajnal A (2005) Too much of a good thing: neurobiology of non-homeostatic eating and drug abuse. Physiol Behav 86(1–2):5–8 46. Shin A, Zheng H, Berthoud H (2009) An expanded view of energy homeostasis: neural integration of metabolic, cognitive, and emotional drives to eat. Physiol Behav 97(5):572–580 47. Kos K, Harte AL, da Silva NF et al (2007) Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J Clin Endocrinol Metab 92:1129–1136 48. Maddineni S, Metzger S, Oco´n O et al (2005) Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology 146:4250–4256 49. Wilkinson M, Brown R, Imran SA et al (2007) Adipokine gene expression in brain and pituitary gland. Neuroendocrinology 86:191–209 50. Fry M, Smith PM, Hoyda TD et al (2006) Area postrema neurons are modulated by the adipocyte hormone adiponectin. J Neurosci 26:9695–9702 51. Guillod-Maximin E, Roy AF, Vacher CM et al (2009) Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons. J Endocrinol 200:93–105 52. Kubota N, Yano W, Kubota T et al (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6:55–68 53. Berg AH, Combs TP, Du X et al (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953 54. Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946 55. Shklyaev S, Aslanidi G, Tennant M et al (2003) Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci USA 100:14217–14222 56. Tomas E, Tsao TS, Saha AK et al (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313
123
10 57. Qi Y, Takahashi N, Hileman SM et al (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10:524–529 58. Coope A, Milanski M, Arau´jo EP et al (2008) AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus. FEBS Lett 582:1471–1476 59. Brichard SM, Delporte ML, Lambert M (2003) Adipocytokines in anorexia nervosa: a review focusing on leptin and adiponectin. Horm Metab Res 35:337–342
123
Eat Weight Disord (2014) 19:3–10 60. Kern PA, Di Gregorio GB, Lu T et al (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52(7):1779–1785 61. Agnello E, Malfi G, Costantino AM (2012) Tumour necrosis factor alpha and oxidative stress as maintaining factors in the evolution of anorexia nervosa. Eat Weight Disord 17(3):e194–e199
