Psychoneuroendocrinology 143 (2022) 105842

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Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

NUCB2/nesfatin-1 is associated with severity of eating disorder symptoms

in female patients with obesity
Elena Weibert a, b, 1, Tobias Hofmann a, b, 1, Ulf Elbelt a, b, c, d, Matthias Rose a, b, e,
Andreas Stengel a, b, f, *
a
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
b
Charité Center for Internal Medicine and Dermatology, Department of Psychosomatic Medicine, Corporate member of Freie Universität Berlin and Humboldt-Universität
zu Berlin, Germany
c
Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin,
Germany
d
Endokrinologikum Berlin, Berlin, Germany
e
Quantitative Health Sciences, Outcomes Measurement Science, University of Massachusetts Medical School, Worcester, MA, USA
f
Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Nesfatin-1 has been described as an anorexigenic peptide. Comprehensive evidence also points to­
Gut-brain axis wards an involvement of nesfatin-1 in the modulation of emotional pathways with a sex-specific regulation of
Psychoendocrinology nesfatin-1 in association with anxiety. Although the implication of nesfatin-1 in the regulation of food intake is
Psychometric
well-established in animals, data in humans are lacking. Therefore, we investigated a possible association of
Psychosomatic
Sex differences
circulating NUCB2/nesfatin-1 with eating disorder symptoms in female and male patients displaying a wide
Stress range of body weight.
Methods: We enrolled 243 inpatients (177 female, 66 male) hospitalized due to anorexia nervosa (n = 66) or
obesity (n = 144) or with normal weight and suffering from somatoform, adjustment, depressive or anxiety
disorders (n = 33). Plasma samples (NUCB2/nesfatin-1 levels measured by ELISA) and measures of eating dis­
order symptoms (by EDI-2, range 0–100) were obtained within three days after admission.
Results: The study population displayed a distinct prevalence of eating disorder symptoms with female patients
with anorexia nervosa (+ 77.0%, p < 0.001) and obesity (+ 87.9%, p < 0.001) reported significantly higher EDI-
2 scores than normal weight patients of the same sex. Accordingly, males with anorexia nervosa (+ 39.7%, p <
0.05) and obesity (+ 51.7%, p < 0.001) had significantly higher EDI-2 scores than males with normal weight.
Within the same BMI group, women displayed significantly higher scores than men (+ 21.4%, p < 0.05 in pa­
tients with anorexia nervosa, + 18.8%, p < 0.001 in participants with obesity). We observed a positive corre­
lation between NUCB2/nesfatin-1 levels and EDI-2 total scores in female patients with obesity (r = 0.285, p =
0.015), whereas no associations were found in other subgroups. A positive correlation between NUCB2/nesfatin-
1 levels and BMI was only observed in the male study population (r = 0.315, p = 0.018).
Conclusions: NUCB2/nesfatin-1 plasma levels were positively associated with EDI-2 total scores in women with
obesity, while no association was observable in men. The lacking association of NUCB2/nesfatin-1 and EDI-2
total scores in female patients with anorexia nervosa might be due to already low NUCB2/nesfatin-1 plasma
levels. Whether NUCB2/nesfatin-1 is selectively involved in eating behavior in women with obesity will have to
be further investigated.

* Corresponding author at: Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
E-mail address: [email protected] (A. Stengel).
1
authors contributed equally to this work

https://doi.org/10.1016/j.psyneuen.2022.105842
Received 4 April 2022; Received in revised form 8 June 2022; Accepted 14 June 2022
Available online 17 June 2022
0306-4530/© 2022 Elsevier Ltd. All rights reserved.

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E. Weibert et al. Psychoneuroendocrinology 143 (2022) 105842

1. Introduction nesfatin-1 plasma levels has been investigated in several studies and
contradictory results have been reported with negative (Alotibi et al.,
Nesfatin-1 is an 82-amino-acid peptide hormone which was first 2019; Demir Çaltekin et al., 2021; Kim et al., 2019), positive (Gutierrez
discovered in the rat hypothalamus in 2006 (Oh-I et al., 2006) and et al., 2020; Saldanha et al., 2012) or no significant correlation (Amanat
displays its characteristic functions after cleavage from its precursor et al., 2020; Hofmann et al., 2015a, 2015b, 2013; Xu et al., 2021). Fe­
protein nucleobindin2 (NUCB2) (Oh-I et al., 2006; Rupp and Stengel, males suffering from restricting-type anorexia nervosa displayed lower
2022) NUCB2/nesfatin-1 (most immunohistochemical studies do not NUCB2/nesfatin-1 levels than a normal weight control group (Atsuchi
distinguish between NUCB2 and nesfatin-1, therefore in the current text et al., 2010; Ogiso et al., 2011), whereas other studies described
we refer to the detected peptide(s) as NUCB2/nesfatin-1) is expressed in significantly higher circulating NUCB2/nesfatin-1 in subjects with un­
several areas of the central nervous system as well as in peripheral tis­ derweight in comparison to controls (Kaba et al., 2015; Mirakhor
sues. In the central nervous system of animals, NUCB2/nesfatin-1 has Samani et al., 2019). Patients with obesity displayed decreased
been localized in the hypothalamus (Goebel et al., 2009a, 2011; Oh-I NUCB2/nesfatin-1 plasma levels following bariatric surgery using
et al., 2006; Scharner et al., 2017; Stengel et al., 2010), brainstem different methods [biliopancreatic diversion with duodenal switch
(Goebel-Stengel et al., 2011; Goebel et al., 2009b, 2011; Oh-I et al., (St-Pierre et al., 2016) or gastric bypass and sleeve gastrectomy (Lee
2006; Stengel et al., 2010) as well as in the amygdala (Goebel et al., et al., 2013)].
2009a) and sympathetic and parasympathetic neurons (Goebel-Stengel Mounting evidence points towards an involvement of nesfatin-1 in
et al., 2011; Goebel et al., 2009a). In humans, the Edinger-Westphal the endocrine modulation of emotional stress responses or an implica­
nucleus, the bed nucleus of the stria terminalis (BNST) as well as tion in mental diseases as depression or anxiety disorders (Emmerzaal
several brainstem areas (e. g. the nucleus of the solitary tract, dorsal and Kozicz, 2013; Weibert et al., 2019). Early on, an anxiogenic effect of
motor nucleus of vagus or locus coeruleus) have been identified as nesfatin-1 has been observed, since icv administration of nesfatin-1 or
expression sites of NUCB2/nesfatin-1 (Bloem et al., 2012; Pałasz et al., nesfatin-130–59 (active core of nesfatin-1) induced anxiety-like (Kühne
2019; Psilopanagioti et al., 2020). Peripherally, NUCB2/nesfatin-1 et al., 2018; Merali et al., 2008) and depression-like behavior in male
expression sites encompass pituitary (Goebel-Stengel and Wang, rats (Kühne et al., 2018). Current findings have demonstrated, that also
2013), adipose tissue (Ramanjaneya et al., 2010), cardiomyocytes (Su ip administration of nesfatin-1 induces anxiety-like (Ge et al., 2015a) as
et al., 2021), testis (Ranjan et al., 2019) as well as the pancreatic well as depression-like (Ge et al., 2015b) behaviors in male rats. Addi­
beta-cells (co-localized with insulin) in humans (Foo et al., 2010) and tionally, the blockage of central nesfatin-1 by icv administration of an
rodents (Yang et al., 2019). Moreover, NUCB2/nesfatin-1 has been anti-nesfatin-1-antibody decreased anxiety-like behavior (Schalla et al.,
detected in gastric X/A-like cells of the rat (Stengel et al., 2009b) and in 2020b). Moreover, restraint stress has been reported to activate
the human analogue, gastric P/D1 cells (Stengel et al., 2013), where it NUCB2/nesfatin-1 neurons in rats (Goebel et al., 2009b) as well as to
has been observed to be co-expressed with ghrelin. As NUCB2/nesfatin-1 increase circulating NUCB2/nesfatin-1 levels (Schalla et al., 2020a),
expression levels are much higher in the rat stomach than in the brain further suggesting nesfatin-1 to play a role in pathways implicated in the
(Stengel et al., 2009b), the stomach has been assumed to be the major emotional stress response.
source of peripherally secreted NUCB2/nesfatin-1. In humans, elevated NUCB2/nesfatin-1 plasma levels have been re­
While the receptor mediating the effects of NUCB2/nesfatin-1 is not ported in mixed-sex populations with panic disorder (Bez et al., 2010),
yet characterized, several studies point toward a G protein-coupled re­ obsessive compulsive disorder (Bez et al., 2012) as well as major
ceptor (Brailoiu et al., 2007; Ishida et al., 2012; Iwasaki et al., 2009; depression (Ari et al., 2011; Xia et al., 2018) as compared to healthy
Pham et al., 2021; Rupp et al., 2021). The central and peripheral controls, indicating a positive correlation between peripheral
localization of the potential nesfatin-1 receptor was recently hypothe­ NUCB2/nesfatin-1 and the severity of depression (Algul and Ozcelik,
sized by autoradiography in rats (Prinz et al., 2016) showing a wide 2018; Xiao et al., 2018; Xu et al., 2018). Interestingly and contradictory
distribution of 125I-nesfatin-1 binding in cerebral tissue (cortex, para­ at the first glance, a study with only male patients diagnosed with
ventricular nucleus of the hypothalamus, area postrema, dorsal motor generalized anxiety disorder reported decreased NUCB2/nesfatin-1
nucleus of the vagus nerve, cerebellum), in the gastrointestinal tract plasma levels (Gunay et al., 2012). However, in line with these results
(gastric mucosa of corpus and antrum, duodenum, jejunum, ileum), in and reconciling previous results, we previously observed a negative
endocrine organs (pituitary, pancreas, adrenal gland, testis, visceral correlation of peripheral NUCB2/nesfatin-1 levels with anxiety in male
adipose tissues) as well as in the heart, skeletal muscle, lung, liver and subjects with obesity (Hofmann et al., 2015b) and a positive correlation
kidney (Prinz et al., 2016). This broad possible localization of the with depressiveness, anxiety and perceived stress in females with
nesfatin-1 receptor gives rise to a pleiotropic action of the peptide in line obesity (Hofmann et al., 2015b, 2013). Additionally, a positive rela­
with the several effects described over the past years. tionship was observed with anxiety scores also in women with anorexia
Since intracerebroventricular (icv) administration of nesfatin-1 leads nervosa (Hofmann et al., 2015a) giving rise to a sex-specific peripheral
to a reduction in food intake (Oh-I et al., 2006) and a delay in gastric regulation of NUCB2/nesfatin-1, which is mirrored also on the cerebral
emptying (Özdemir-Kumral et al., 2021; Stengel et al., 2009a), level (Bloem et al., 2012). However, the cerebral relationships are in­
nesfatin-1 has been primarily suggested to be a potent anorexigenic verse with increased brain NUCB2 mRNA levels in male and decreased
peptide. However, following intraperitoneal (ip) injection of nesfatin-1, levels in female suicide victims compared to controls (Bloem et al.,
anorexigenic effects could not be observed (Stengel et al., 2009a) or only 2012) warranting further investigations on the sex-specific regulation of
after administration of very high doses (Shimizu et al., 2009), pointing NUCB2/nesfatin-1.
towards a primarily brain-mediated anorexigenic effect. As Considering the fact that nesfatin-1 is involved in the regulation of
NUCB2/nesfatin-1 is co-localized with several neurotransmitters emotional processes and food intake, it is reasonable to focus on this
involved in the regulation of food intake like neuropeptide interrelation, since emotional state and eating habits seem to be closely
Y/Agouti-related protein (NPY/AgRP), oxytocin, cocaine- and interlinked in eating and weight regulation disorders. Previously, we
amphetamine-regulated transcript (CART), cholecystokinin (CCK-8S), demonstrated that female patients with anorexia nervosa with high
melanin-concentrating hormone (MCH) or leptin (Goebel-Stengel and anxiety scores also exhibit more severe eating disorder symptoms as
Wang, 2013; Pałasz et al., 2020; Psilopanagioti et al., 2020), the assessed by the Eating Disorder Inventory-2 (EDI-2), although we
anorexigenic effect of nesfatin-1 might be mediated by influencing the observed no correlation of plasma NUCB2/nesfatin-1 with EDI-2 scores
signaling of these neurotransmitters in the central nervous system in this population (Hofmann et al., 2015a). In the present study we
(Pałasz et al., 2020). investigated whether circulating NUCB2/nesfatin-1 levels are associated
In humans, the association of body mass index (BMI) and NUCB2/ with eating disorder symptoms in patients with a wide range of body

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E. Weibert et al. Psychoneuroendocrinology 143 (2022) 105842

weight and different intensities of eating disorder symptoms and (ELISA, catalog # EK-003–26, Phoenix Pharmaceuticals, Inc., Burlin­
whether this is dependent on BMI. Taking into consideration the game, CA, USA) according to the manufacturer’s instructions. All sam­
assumed sex-specific regulation of NUCB2/nesfatin-1 in anxiety, we also ples were processed in one batch; the intra-assay variability was 9.6%.
aimed to assess possible differences in the manifestation of impaired The antibody used in this ELISA, as in most commercially available kits,
eating behavior between women and men. is directed against nesfatin-1 and therefore also recognizes full length
NUCB2 containing the epitope. Considering this, in the text we refer to
2. Materials and methods the detected peptide(s) as NUCB2/nesfatin-1.

2.1. Subjects 2.3. Anthropometric measurements

In the present study, a total of 177 female and 66 male inpatients (n For calculation of BMI (as kg/m2) height and body weight of the
= 243) admitted to the Department of Psychosomatic Medicine at participants wearing light underwear were assessed at the same day of
Charité – Universitätsmedizin Berlin between September 2010 and blood withdrawal between 07:00–08:00 in the morning.
September 2015 were enrolled. The study population consisted of three
different patient populations: 1) patients exhibiting normal weight (n = 2.4. Patient-reported outcomes
33; 19 women, 14 men) and hospitalized due to somatoform, adjust­
ment, depressive or anxiety disorders; 2) patients diagnosed with typical The presence of eating disorder symptoms was assessed using the
or atypical anorexia nervosa (n = 66; 62 women, 4 men); 3) patients Eating Disorder Inventory (EDI). This self-report questionnaire was
with obesity (n = 144; 96 women, 48 men), hospitalized for the treat­ established to determine the severity of eating disorder symptoms in
ment of somatic and mental comorbidities, the initiation of weight bulimia nervosa, anorexia nervosa and eating disorders not otherwise
reduction or the further evaluation prior to bariatric surgery. specified meanwhile including binge eating disorder (Garner et al.,
The inclusion criterion for patients with obesity was a BMI of ≥ 30 1983). The EDI comprises 64 questions and is divided into eight sub­
kg/m2. Inclusion criteria for inpatients with underweight were a BMI scales evaluating “drive for thinness”, “bulimia”, “body dissatisfaction”,
with a maximum of 18.5 kg/m2 and fulfilment of the diagnostic criteria “ineffectiveness”, “perfectionism”, “interpersonal distrust”, “interocep­
for typical or atypical anorexia nervosa according to ICD-10 (Interna­ tive awareness” and “maturity fears” (Garner et al., 1983). In the first
tional Statistical Classification of Diseases and Related Health Problems revision the three subscales “asceticism”, “impulse regulation” and
of the World Health Organization, 10th revision) (World Health Orga­ “social insecurity” were added (EDI-2) (Garner, 1991). The EDI-2 is a
nization, 2004). Patients with typical anorexia nervosa displayed a BMI validated self-report instrument and is widely used in the clinical setting
≤ 17.5 kg/m2, self-induced weight loss, body image distortion and for assessment of eating disorder symptoms and its changes during
amenorrhea (World Health Organization, 2004). In contrast, the subtype therapy as well as in epidemiological studies (Thiel and Paul, 2005). In
of atypical anorexia nervosa did not fulfill all key symptoms required for previous studies, a high test-retest reliability (Thiel and Paul, 2006) and
typical anorexia nervosa in ICD-10 (e.g., the absence of amenorrhea or a internal consistency (Nevonen et al., 2006; Norring and Sohlberg, 1988;
BMI between 17.5 and 18.5 kg/m2). The inclusion criterion for patients Norring, 1990) have been demonstrated. Using portable electronic de­
with normal weight was a BMI of 18.5–25.0 kg/m2. vices, we handed out the German version of EDI-2 (Thiel et al., 1997) but
Exclusion criteria for all subgroups were an age of less than 18 years, only used the above mentioned first 8 subscales of the EDI leaving out
functional or somatoform disorders of the gastrointestinal tract (e.g., the subscales “asceticism”, “impulse regulation” and “social insecurity”.
irritable bowel syndrome), current pregnancy, untreated psychotic dis­ The patients completed the questionnaire between one day before and
order, current malignant disease or previous bariatric surgery. Patients five days after blood collection. Cronbach’s alpha ranged from 0.74 to
with obesity and hypercortisolism or untreated hypothyreoidism were 0.92 for the eight subscales assessed in the present study population The
also excluded from the study. Some of the patients included in this study scores of all scales were added and converted into percentage values.
also participated in our previous projects investigating the correlation
between NUCB2/nesfatin-1 and anxiety (Hofmann et al., 2015a, 2015b, 2.5. Statistical analysis
2013, 2017).
All patients gave written informed consent and all investigations in All data are expressed as mean ± standard deviation (SD). The dis­
the present study were conducted in accordance with the Declaration of tribution of collected data was determined by the Kolmogorov-Smirnov
Helsinki. The study was approved by the institutional ethics committee test. Correlations were determined by Pearson’s or Spearman’s analyses
of the Charité – Universitätsmedizin Berlin (protocol number: EA1/114/ depending on the distribution of the data. Differences in outcome vari­
10). ables between two groups were analyzed using t-test and between three
groups using one-way ANOVA followed by Tamhane T2 as post hoc test.
2.2. Laboratory analyses Differences for categorical variables were analyzed using chi square test.
Differences between correlations and groups were considered statisti­
After an overnight fasting period, venous blood was taken from a cally significant when p < 0.05. All statistical analyses were conducted
forearm vein between 07:00 and 08:00 in the morning. In order to using IBM SPSS Statistics 27 (IBM, Armonk, NY, USA) and SigmaStat 3.1
prevent an influence of treatment on psychometric, metabolic and (Systat Software, San Jose, CA, USA).
hormonal parameters, blood samples were obtained from the patients
within five days after hospital admission. Patients were allowed to drink 3. Results
small amounts of water but were advised not to drink larger amounts or
other beverages, or to eat, smoke or exercise before blood withdrawal. 3.1. Demographic, socioeconomic, and medical characteristics
Blood was collected in pre-cooled standard EDTA tubes containing
aprotinin (1.2 Trypsin Inhibitory Unit/ml blood; ICN Pharmaceuticals, Characteristics of the study population are presented in Table 1. Both
Costa Mesa, CA, USA) for peptidase inhibition. Directly after blood males and females suffering from anorexia nervosa (14.4 ± 1.5 and 14.2
collection, the EDTA tubes were stored on ice and then centrifuged for ± 2.1 vs. 22.3 ± 1.9 and 21.2 ± 1.8 kg/m2; p < 0.001, Table 1) and
10 min at 3000 g and at 4 ◦ C. Plasma was then separated and stored at − obesity (48.2 ± 9.5 and 49.8 ± 9.3 vs. 22.3 ± 1.9 and 21.2 ± 1.8 kg/m2;
80 ◦ C until further processing. p < 0.001, Table 1) differed significantly in terms of BMI in comparison
The measurements of plasma NUCB2/nesfatin-1 levels took place in to the normal weight group of the same sex. Accordingly, participants
01/2016 using a commercial enzyme-linked immunosorbent assay with anorexia nervosa had a significantly lower BMI than patients with

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E. Weibert et al. Psychoneuroendocrinology 143 (2022) 105842

Table 1 Table 1 (continued )

Demographic and socioeconomic characteristics, comorbidities and medication Parameter Anorexia Normal Obesity
of study patients. nervosa weight (♀ n = 96, ♂ n
Parameter Anorexia Normal Obesity (♀ n = 62, ♂ (♀ n = 19, ♂ = 48)
nervosa weight (♀ n = 96, ♂ n n = 4) n = 14)
(♀ n = 62, ♂ (♀ n = 19, ♂ = 48) - without school-leaving 0 (0.0%) 1 (7.1%) 4 (8.5%)
n = 4) n = 14) qualification
Women Currently employed 3 (75.0%) 6 (42.9%) 15 (31.3%)
Demographic characteristics Unemployment during past 5 0 (0.0 %) 5 (35.7%) 22 (46.8%)
Age 26.6 ± 42.9 ± 15.3 44.4 ± 12.7 years
8.4***, yyy, # Comorbidities
BMI 14.2 ± 21.2 ± 1.8 49.8 ± 9.3*** Binge eating disorder 0 (0.0%) 0 (0.0%) 7 (14.6%)
2.1***, yyy Bulimia nervosa 0 (0.0%) 0 (0.0%) 0 (0.0%)
Socioeconomic characteristics Sleep-associated breathing 0 (0.0%) 0 (0.0%) 27
Living in a partnership 17 12 (63.2%) 47 (49.0%) disorder (57.4%)þþþ
(27.4%)þþ Type 2 diabetes mellitus 0 (0.0%) 0 (0.0%) 17 (35.4%)þþ
Level of education Type 1 diabetes mellitus 0 (0.0%) 0 (0.0%) 1 (2.1%)
- university entrance diploma 21 (33.9%) 8 (42.1%) 14 Impaired fasting glucose 0 (0.0%) 0 (0.0%) 7 (14.6%)
(‘Abitur’) (14.6%)þþþ Insulin resistance (with 0 (0.0%) 0 (0.0%) 11 (22.9%)
- vocational diploma 4 (6.5%) 2 (10.5%) 4 (4.2%) preserved glycaemic control)
(‘Fachabitur’) Arterial hypertension 0 (0.0%) 3 (21.4%) 34
- secondary education 26 (41.9%) 7 (36.8%) 47 (49.0%) (70.8%)þþþ
certificate (‘Mittlere Reife’) Hypercholesterinemia 1 (25.0%) 8 (57.1%) 28 (58.3%)
- basic school qualification 10 (16.1%) 1 (5.3%) 24 (25.0%) Hypertriglyceridemia 0 (0.0%) 1 (7.1%) 18 (37.5%)
(‘Hauptschulabschluss’) Hyperuricemia 0 (0.0%) 1 (7.1%) 20 (41.7%)
- without school-leaving 1 (1.6%) 1 (5.3%) 7 (7.3%) Fatty liver disease 0 (0.0%) 1 (7.1%) 34
qualification (72.3%)þþþ
Currently employed 21 (33.9%) 15 43 (44.8%) Medication
(78.9%)þþ Insulin 0 (0.0%) 0 (0.0%) 10 (20.8%)
Unemployment during past 5 24 (38.7%) 4 (21.1%) 47 (49.0%) DPP-4-antagonists/GLP-1- 0 (0.0%) 0 (0.0%) 4 (8.3%)
years analogues
Comorbidities Other antidiabetics 0 (0.0%) 0 (0.0%) 13 (27.1%)
Binge eating disorder 0 (0.0%) 0 (0.0%) 17 Psychopharmacological 2 (50.0%) 3 (21.4%) 10 (20.8%)
(17.7%)þþþ treatment
Bulimia nervosa 0 (0.0%) 0 (0.0%) 1 (1.0%)
Statistical analyses: t-tests. Data are expressed as mean ± SD. Differences be­
Sleep-associated breathing 0 (0.0%) 0 (0.0%) 43 (46.2
tween two groups were assessed using the t-test, between three groups using
disorder %)þþþ
Type 2 diabetes mellitus 0 (0.0%) 0 (0.0%) 23 (24.0 one-way ANOVA or chi square test. Significant differences are displayed in bold
%)þþþ (* p < 0.05, ** p < 0.01 and *** p < 0.001 vs. normal weight group of same sex;
Type 1 diabetes mellitus 0 (0.0%) 0 (0.0%) 0 (0.0%) †p < 0.05, ††p < 0.01 and ††† p < 0.001 vs. obesity group of same sex; # p < 0.05
Impaired fasting glucose 0 (0.0%) 0 (0.0%) 8 (8.3 %)þþ vs. other sex of same BMI group, + p < 0.05, ++ p < 0.01 and +++ p < 0.001 vs.
Insulin resistance (with 0 (0.0%) 0 (0.0%) 22 (23.2 normal weight and anorexia nervosa group of same sex). Abbreviations: BMI,
preserved glycaemic control) %)þþþ body mass index.
Arterial hypertension 1 (1.6%) 1 (5.3%) 56 (58.9
%)þþþ
Hypercholesterinemia 20 (32.8%) 13 (68.4%) 48 (50.0%) obesity (p < 0.001, Table 1).
Hypertriglyceridemia 0 (0.0%) 0 (0.0%) 18 Regarding the socioeconomic status among female subjects, the
(18.8%)þþþ proportion of women living in a partnership was lowest in the subpop­
Hyperuricemia 4 (7.7%) 1 (5.3%) 39
ulation with anorexia nervosa (27.4%; p < 0.01, Table 1). Level of ed­
(40.6%)þþþ
Fatty liver disease 0 (0.0%) 0 (0.0%) 57 ucation was significantly lower in the group with obesity with less
(60.6%)þþþ women having received a university diploma (14.6%, p < 0.001,
Medication Table 1). Women with normal weight were more likely to be currently
Insulin 0 (0.0%) 0 (0.0%) 6 (6.3%)
employed (78.9%, p < 0.01, Table 1) and generally had higher school
DPP-4-antagonists/GLP-1- 0 (0.0%) 0 (0.0%) 2 (2.1%)
analogues
qualifications. In the male study population, no significant differences
Other antidiabetics 0 (0.0%) 0 (0.0%) 24 were observed regarding socioeconomic status and education.
(25.0%)þþþ In terms of comorbidities and medication, men and women with
Psychopharmacological 20 (32.3%) 4 (21.1%) 38 (39.6%) obesity suffered more often from binge eating disorder, sleep-associated
treatment
breathing disorder, impaired fasting glucose, insulin resistance, type 2
Men
Demographic characteristics diabetes mellitus, arterial hypertension, hypertriglyceridemia, hyper­
Age 38.3 ± 36.3 ± 11.9 45.0 ± 14.0 uricemia and fatty liver disease (Table 1). Within this group, insulin
14.6# therapy was taken by 6.3% of the female and 20.8% of the male subjects.
BMI 14.4 ± 22.3 ± 1.9 48.2 ± 9.5***
DPP-4-antagonists and GLP-1-analogues with 2.1% and 8.3%, respec­
1.5***, yyy
Socioeconomic characteristics
tively each played a minor role. About one quarter of the population
Living in a partnership 1 (25.0%) 7 (50.0%) 19 (39.6%) with obesity (women: 25.0%, men: 27.1%) used other antidiabetics (e.
Level of education g., metformin). However, no significant differences between the three
- university entrance diploma 2 (50.0%) 5 (35.7%) 12 (25.5%) groups were observed for hypercholesterinemia and the use of psycho­
(‘Abitur’)
tropic drugs (Table 1). When comparing NUCB2/nesfatin-1 plasma
- vocational diploma 0 (0.0%) 1 (7.1%) 3 (6.4%)
(‘Fachabitur’) levels of patients on antidiabetic therapy and of patients without this
- secondary education 1 (25.0%) 5 (35.7%) 13 (27.7%) medication no difference in NUCB2/nesfatin-1 plasma levels was
certificate (‘Mittlere Reife’) detected between groups (data not shown).
- basic school qualification 1 (25.0%) 2 (14.3%) 15 (31.9%)
(‘Hauptschulabschluss’)

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3.2. Women display a higher burden of eating disorder symptoms than and “ineffectiveness” as well as “body dissatisfaction” in men with
men anorexia nervosa (Table 2).
Both females with anorexia nervosa and obesity showed significantly
Women with anorexia nervosa displayed a significantly higher EDI-2 higher EDI-2 total scores than males of the same BMI subgroup (+ 21.4
total score than the control group of the same sex (+ 77.0%, p < 0.001, %, p < 0.05 and + 18.8%, p < 0.001, Table 2) indicating a higher burden
Table 2). The difference was reflected by significantly higher scores in of eating disorder symptoms in women.
all subscales except “perfectionism” (Table 2). Likewise, EDI-2 total
scores in the group with obesity were significantly higher than in women 3.3. Positive correlation between peripheral NUCB2/nesfatin-1 and BMI
with normal weight (+ 87.9%, p < 0.001, Table 2). There were no dif­ in men across all BMI subgroups
ferences regarding the subscales “perfectionism” and “maturity fears”
(Table 2). Additionally, scores in the subscales “body dissatisfaction” There was no difference in NUCB2/nesfatin-1 plasma levels ac­
and “interoceptive awareness” (- 37.8%, p < 0.001; + 23.6%, p < 0.05, cording to the three groups in men and women (women: anorexia
Table 2) significantly differed between females with anorexia nervosa nervosa vs. normal weight vs. obesity, 0.44 ± 0.51 ng/ml vs. 0.49 ±
and obesity. 0.49 ng/ml vs. 0.51 ± 0.51 ng/ml, p > 0.05; men: anorexia nervosa vs.
In the male subgroups, significantly higher EDI-2 total scores were normal weight vs. obesity, 0.26 ± 0.25 ng/ml vs. 0.30 ± 0.20 ng/ml vs.
observed in men with anorexia nervosa and obesity in comparison to the 0.50 ± 0.43 ng/ml, p > 0.05; Table 2).
control group (+ 39.7 %, p < 0.05 and + 51.7 %, p < 0.001, Table 2). Considering the whole study population, NUCB2/nesfatin-1 levels
The differences were particularly related to the subscales “drive for were negatively correlated with age in men (r = − 0.353, p = 0.008,
thinness”, “bulimia” and “body dissatisfaction” in males with obesity Table 3) but not in women (r = − 0.086, p = 0.321, Table 3). Regarding
the subgroups, NUCB2/nesfatin-1 levels were negatively correlated with
Table 2 age in females with normal weight (r = − 0.507, p = 0.038, Table 3) and
Anthropometric and psychometric parameters according to BMI subgroups in males with obesity (r = − 0.481, p = 0.001, Table 3).
women and men. A positive association between NUCB2/nesfatin-1 levels and BMI
Parameter Anorexia Normal weight Obesity
was observed in males (r = 0.315, p = 0.018, Table 3), while in females
nervosa (♀ n = 19, ♂ n = (♀ n = 96, ♂ n = no association was detected (r = 0.087, p = 0.319, Table 3). There was
(♀ n = 62, ♂ n = 14) 48) no significant correlation between peripheral NUCB2/nesfatin-1 and
4) BMI regarding the subgroups of both sexes.
Women
Age 26.6 ± 8.4***, 42.9 ± 15.3 44.4 ± 12.7 3.4. Positive correlation between NUCB2/nesfatin-1 plasma levels and
yyy, #
***, ***
EDI-2 total score in women with obesity
BMI 14.2 ± 2.1 21.2 ± 1.8 49.8 ± 9.3
yyy

NUCB2/nesfatin-1 0.44 ± 0.51 0.49 ± 0.49 0.51 ± 0.51 In patients with anorexia nervosa, no association between NUCB2/
EDI-2 total 45.3 ± 17.2***, 25.6 ± 10.7 48.1 ± 10.7***, nesfatin-1 and EDI-2 total score was observed, neither in females (r =
# ###
0.069, p = 0.653, Fig. 1A, Table 3) nor in the very small subgroup of four
• drive for thinness 49.7 ± 32.9*** 14.7 ± 15.3# 59.8 ± 19.7***,
# males (r = 0.129, p = 0.871, Fig. 1B, Table 3). Furthermore, no corre­
• bulimia 19.5 ± 26.2*** 3.9 ± 5.2 26.0 ± 19.6*** lation between NUCB2/nesfatin-1 plasma levels and EDI-2 total score
• body dissatisfaction 56.9 ± 21.8***, 25.2 ± 15.2 91.5 ± 12.4***, were detected in female (r = − 0.024, p = 0.928, Fig. 1C, Table 3) and
###
male (r = − 0.133, p = 0.697, Fig. 1D, Table 3) patients with normal
yyy

• ineffectiveness 46.6 ± 23.7** 29.5 ± 15.1 40.5 ± 20.6*, ##

weight. However, female patients with obesity displayed a significant
• perfectionism 46.5 ± 19.7 38.4 ± 18.5 40.9 ± 20.0
• interpersonal 46.2 ± 19.9* 34.1 ± 15.2 44.5 ± 18.5*
positive correlation between peripheral NUCB2/nesfatin-1 and EDI-2
distrust total score (r = 0.285, p = 0.015, Fig. 1E, Table 3) with further posi­
• interoceptive 44.0 ± 20.0***, 21.6 ± 15.5 35.6 ± 16.8**, tive associations with the subscales “bulimia” (r = 0.241, p = 0.042,
##
awareness y
Table 3), and “interoceptive awareness” (r = 0.311, p = 0.008, Table 3).
• maturity fears 49.5 ± 22.5* 37.5 ± 13.7 42.3 ± 15.8
This relationship was absent in male patients with obesity (r = − 0.103,
Men
Age 38.3 ± 14.6# 36.3 ± 11.9 45.0 ± 14.0 p = 0.523, Fig. 1F, Table 3).
BMI 14.4 ± 1.5***, 22.3 ± 1.9 48.2 ± 9.5***
4. Discussion
yyy

NUCB2/nesfatin-1 0.26 ± 0.25 0.30 ± 0.20 0.50 ± 0.43

EDI-2 total 37.3 ± 5.1*, #
26.7 ± 7.2 40.5 ± 12.4***,
### While studies in animal models reported a regulatory effect of
• drive for thinness 22.9 ± 21.0 6.5 ± 5.8# 51.7 ± 21.2***, nesfatin-1 on food intake (Oh-I et al., 2006; Stengel et al., 2009a), some
#
studies conducted in humans observed an association with BMI (Alotibi
• bulimia 13.6 ± 18.0 3.5 ± 3.9 23.0 ± 19.9*** et al., 2019; Demir Çaltekin et al., 2021; Gutierrez et al., 2020; Kim et al.,
• body dissatisfaction 47.8 ± 8.2**, yy
24.9 ± 11.5 75.0 ± 20.3***,
### 2019; Saldanha et al., 2012), which may also suggest an effect on eating
• ineffectiveness 45.5 ± 6.4*, y
30.9 ± 16.1 30.0 ± 20.6## behavior. However, empirical data have been lacking. In the present
• perfectionism 30.8 ± 20.4 40.2 ± 14.2 42.8 ± 21.2 study we investigated the association of NUCB2/nesfatin-1 plasma
• interpersonal 46.4 ± 15.2 42.3 ± 18.2 39.5 ± 17.3 levels with the severity of eating disorder symptoms across a wide range
distrust of BMI and in accordance with sex. The results showed a significant
• interoceptive 41.0 ± 10.9 25.1 ± 13.2 26.5 ± 19.8##
awareness
positive correlation between NUCB2/nesfatin-1 concentration and
• maturity fears 41.3 ± 13.6 39.8 ± 14.1 37.1 ± 15.4 EDI-2 total scores in female patients with obesity. No associations were
observed in males of all three weight subgroups and in female patients
Statistical analysis: Data are expressed as mean ± standard deviation. Differ­
with anorexia nervosa and normal weight. In addition,
ences between two groups were assessed using the t-test, between three groups
using one-way ANOVA. Significant differences are displayed in bold (* p < 0.05, NUCB2/nesfatin-1 plasma levels were positively associated with BMI
** p < 0.01 and *** p < 0.001 vs. normal weight group of same sex; † p < 0.05, †† and negatively with age in men but not in women.
p < 0.01 and ††† p < 0.001 vs. obesity group of same sex; # p < 0.05, ## p < In the present study, we observed a positive association between
0.01 and ### p < 0.001 vs. other sex of same BMI group). Abbreviations: BMI, circulating NUCB2/nesfatin-1 levels and the degree of eating disorder
body mass index; EDI-2, eating disorder inventory. symptoms in obese females. Previously, we described that peripheral

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E. Weibert et al. Psychoneuroendocrinology 143 (2022) 105842

Table 3 anxiety in the male population (Hofmann et al., 2015b). In line with
Correlation of NUCB2/nesfatin-1 levels with anthropometric and psychometric these findings, our results provide further evidence for a sex-specific
parameters according to BMI subgroups in women and men. regulation of nesfatin-1 also regarding eating behavior. Up to now
Parameter Both sexes Women Men there is no evidence for a different mode of action of nesfatin-1 in men
Whole population (♀ r p r p r p
and women and whether it is based on a central or peripheral level.
n = 177, ♂ n = 66) Previously, one study detected sex-specific differences in cerebral
Age -0.150 0.038 -0.086 0.321 -0.353 0.008 NUCB2/nesfatin-1 expression in male and female suicide victims with
BMI 0.124 0.088 0.087 0.319 0.315 0.018 depression (Bloem et al., 2012), as NUCB2 mRNA expression in the
EDI-2 total 0.114 0.117 0.135 0.120 -0.002 0.990
midbrain of male suicide victims was elevated compared to controls
• drive for thinness 0.080 0.274 0.091 0.295 0.012 0.932
• bulimia 0.105 0.149 0.124 0.155 0.037 0.787 without mental disorder, whereas in females a decreased
• body dissatisfaction 0.119 0.103 0.101 0.245 0.158 0.245 NUCB2/nesfatin-1 expression was described (Bloem et al., 2012).
• ineffectiveness 0.070 0.340 0.091 0.297 -0.045 0.742 Moreover, peripheral NUCB2/nesfatin-1 levels were found to be higher
• perfectionism -0.001 0.990 0.052 0.552 -0.160 0.239 in women compared to men (Bergmann et al., 2015; Feijóo-Bandín et al.,
• interpersonal 0.078 0.288 0.047 0.592 0.176 0.194
distrust
2013; Hofmann et al., 2015b). However, the peripheral
• interoceptive 0.089 0.222 0.148 0.089 -0.130 0.340 NUCB2/nesfatin-1 levels did not differ between males and females in the
awareness present study.
• maturity fears 0.029 0.688 0.056 0.518 -0.110 0.419 To date, it is unclear, whether central nesfatin-1 is responsible for the
sex-dependent differences and whether the central nervous system is a
Anorexia nervosa (♀ r p r p r p
n = 62, ♂ n = 4) source of circulating NUCB2/nesfatin-1. In rodents, it has been shown
Age 0.105 0.471 0.197 0.193 -0.676 0.324 that the expression of NUCB2/nesfatin-1 is much higher in the stomach
BMI -0.004 0.977 -0.006 0.967 0.185 0.815 than in the brain (Stengel et al., 2009b), so that the stomach has been
EDI-2 total 0.081 0.582 0.069 0.653 0.129 0.871 hypothesized as the major source of peripherally circulating
• drive for thinness 0.137 0.349 0.126 0.410 -0.209 0.791
NUCB2/nesfatin-1. Since the anorexigenic effects of nesfatin-1 were
• bulimia 0.025 0.865 0.026 0.864 -0.336 0.665
• body dissatisfaction 0.201 0.166 0.195 0.199 0.040 0.960 more prominently exerted after central application in rodents compared
• ineffectiveness 0.005 0.974 -0.006 0.968 0.969 0.031 to peripheral administration (Könczöl et al., 2012; Mortazavi et al.,
• perfectionism 0.044 0.765 0.040 0.796 -0.424 0.576 2015; Oh-I et al., 2006; Prinz et al., 2015; Shimizu et al., 2009; Stengel
• interpersonal 0.043 0.771 0.040 0.794 0.142 0.858
et al., 2009a), it remains to be established, how nesfatin-1 exerts its
distrust
• interoceptive 0.048 0.742 0.048 0.754 -0.129 0.871 effects on feeding behavior in humans.
awareness In general, women have a higher lifetime prevalence of mental dis­
• maturity fears -0.036 0.808 -0.067 0.662 0.923 0.077 orders like anxiety disorders or depression than men (Boyd et al., 2015;
Seedat et al., 2009). These internalizing disorders, also including
Normal weight (♀ n r p r p r p
bulimia and anorexia nervosa, are more common in females, whereas
= 19, ♂ n = 14)
Age -0.348 0.076 -0.507 0.038 -0.073 0.831 externalizing disorders, e.g., attention-deficit/hyperactivity disorder or
BMI -0.143 0.469 -0.024 0.927 -0.356 0.283 substance-related disorders are more prevalent in males (Boyd et al.,
EDI-2 total -0.057 0.772 -0.024 0.928 -0.133 0.697 2015; Seedat et al., 2009). In our previous study, the perception of stress,
• drive for thinness -0.051 0.797 -0.095 0.716 -0.577 0.063
anxiety, and depressiveness assessed by self-report tests was signifi­
• bulimia -0.124 0.528 -0.146 0.575 -0.180 0.596
• body dissatisfaction -0.114 0.562 -0.111 0.671 -0.060 0.860
cantly higher in females compared to males with obesity (Hofmann
• ineffectiveness 0.027 0.892 0.128 0.624 -0.237 0.484 et al., 2015b). In the present study, among patients with obesity, women
• perfectionism 0.016 0.934 0.110 0.674 -0.381 0.248 showed comparatively significantly higher EDI-2 scores than men indi­
• interpersonal 0.076 0.700 0.035 0.894 0.694 0.018 cating a higher burden of eating disorder symptoms. Aside from a more
distrust
critical self-perception with body shame and lower self-esteem or
• interoceptive -0.041 0.835 -0.004 0.987 -0.124 0.717
awareness experienced (sexual) violence as examples for risk factors (Kuehner,
• maturity fears -0.203 0.300 -0.206 0.427 -0.237 0.483 2017; Li and Graham, 2017), sex hormones like estradiol and proges­
terone also contribute to a higher vulnerability of women to mental
Obesity (♀ n = 96, ♂ r p r p r p
disorders (Kuehner, 2017; Li and Graham, 2017). This is supported by
n = 48)
Age -0.301 0.001 -0.215 0.069 -0.481 0.001
the fact, that the risk of developing mood disorders is higher during
BMI 0.157 0.100 0.113 0.346 0.243 0.126 hormonal transition periods [e.g., premenstrual syndrome/premenst­
EDI-2 total 0.142 0.133 0.285 0.015 -0.103 0.523 rual dysphoric disorder, postpartum or perimenopausal depression
• drive for thinness 0.004 0.964 0.100 0.416 -0.191 0.231 (Barth et al., 2015)]. Interestingly, sex hormones were described to
• bulimia 0.142 0.133 0.241 0.042 -0.048 0.764
interact with different neurotransmitter systems (e.g., dopamine, sero­
• body dissatisfaction 0.065 0.496 0.105 0.380 0.003 0.988
• ineffectiveness 0.123 0.195 0.184 0.122 -0.008 0.960 tonin) contributing to brain development or neuroplasticity by influ­
• perfectionism -0.026 0.788 0.059 0.626 -0.178 0.266 encing neurotransmitter circuitries (Barth et al., 2015) and thus, shaping
• interpersonal 0.098 0.301 0.065 0.587 0.170 0.288 cognitive behavior.
distrust Since NUCB2/nesfatin-1 is also expressed in organs of the
• interoceptive 0.147 0.121 0.311 0.008 -0.131 0.414
awareness
hypothalamus-pituitary-gonadal (HPG) axis interacting with hormones
• maturity fears 0.120 0.207 0.225 0.058 -0.124 0.439 implicated in reproductive system like testosterone and estrogen
(Schalla and Stengel, 2021), the sex-specific regulation might also arise
Statistical analysis: Correlations were determined by Pearson’s analysis. Sig­
from interrelations based on this axis. In mouse pituitary gland,
nificant associations are displayed in bold. Abbreviations: BMI, body mass index;
EDI-2, eating disorder inventory. administration of testosterone, estradiol and progesterone increased
NUCB2 mRNA, after it was initially decreased following ovariectomy or
castration (Chung et al., 2015; Seon et al., 2017). Interestingly, in
NUCB2/nesfatin-1 positively correlated with scores of perceived stress,
goldfish, NUCB2 mRNA expression in the pituitary decreased after both,
depressiveness, and anxiety in women with obesity, while no association
estradiol, and testosterone ingestion (Bertucci et al., 2016). Conversely,
between NUCB2/nesfatin-1 and the extent of depression and perceived
icv injection of nesfatin-1 reduced gonadotropin-releasing hormone
stress was found in men (Hofmann et al., 2015b, 2013). Interestingly, a
(GnRH) mRNA expression in the hypothalamus in vivo, but increased
negative correlation was observed between NUCB2/nesfatin-1 and
GnRH mRNA and protein expression in mouse cells, when administered

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Fig. 1. Correlation of NUCB2/nesfatin-1 levels with EDI-2 total scores according to BMI subgroups in women and men. Associations were assessed between NUCB2/
nesfatin-1 plasma levels (in ng/ml) and EDI-2 total scores in patients with anorexia nervosa (A = ♀, B = ♂), normal weight (C = ♀, D = ♂) and obesity (E = ♀, F = ♂).
Values for r and p are presented in the figure.

in vitro (Schalla and Stengel, 2021). Similarly, in vitro incubation with NUCB2 mRNA expression rather being upregulated during transition
nesfatin-1 increased mRNA and protein expression of luteinizing hor­ from pubertal to adult animals (Schalla and Stengel, 2021). This might
mone (LH) in murine pituitary cells, whereas icv administration of result in already high NUCB2/nesfatin-1 levels in male adolescents
nesfatin-1 reduced LH mRNA (Schalla and Stengel, 2021). Noteworthy, precluding any positive correlation (de Dios et al., 2019). Thus, our
NUCB2/nesfatin-1 expression was reported to be much higher in the findings concerning the correlation with BMI might be due to the
reproductive organs like ovary and testis than in the hypothalamus (Kim sex-specific regulation. Given the inconsistent results regarding the as­
et al., 2014), e.g. stimulating testosterone or progesterone secretion sociation of NUCB2/nesfatin-1 with BMI (Alotibi et al., 2019; Amanat
(Schalla and Stengel, 2021). The different mode of action of nesfatin-1 et al., 2020; Demir Çaltekin et al., 2021; Gutierrez et al., 2020; Mier­
reported in vivo and in vitro experiments warrants further investigation. zyński et al., 2019; Xiao et al., 2018) as an expression of a long-term
Based on these findings, we could hypothesize, that our observation energetic state, further research is needed to better characterize the
with a positive correlation of NUCB2/nesfatin-1 and eating disorder underlying mechanisms.
symptoms in females but not in males with obesity might be based on a Noteworthy, the significant association of NUCB2/nesfatin-1 and
differential secretion of nesfatin-1 on a cerebral level interacting with eating disorder symptoms was not observable in females with anorexia
sex hormones along the HPG axis. Accordingly, the above-mentioned nervosa despite of comparably high EDI-2 scores to females with obesity.
higher susceptibility of women to mental and specifically eating disor­ Previously, we investigated the correlation between peripheral NUCB2/
ders might be reflected by the positive correlation of eating disorder nesfatin-1 levels and the extent of anxiety in female patients with
pathology (mirrored by EDI-2 total scores) with nesfatin-1 as a peptide anorexia nervosa (Hofmann et al., 2015a). Females displaying high
with anxiogenic and depression-promoting properties (Weibert et al., anxiety scores [according to Generalized Anxiety Disorder 7 question­
2019) with a possible effect on eating habits in women. Whether naire, (GAD-7 (Spitzer et al., 2006)] had 65% higher NUCB2/nesfatin-1
nesfatin-1 has an opposing effect on eating behavior in men should be levels compared to women with less distinctive anxiety symptoms, re­
further investigated. Moreover, the interrelation of nesfatin-1 and sex flected by a positive correlation of NUCB2/nesfatin-1 with GAD-7 scores
hormones especially under conditions of eating disorders requires pro­ (Hofmann et al., 2015a). At the same time, psychometric assessment of
ceeding research, as disturbances in the menstrual cycle (e.g., dys-/a­ eating disorder symptoms was conducted using EDI-2 (Hofmann et al.,
menorrhea) or the postmenopausal period might be confounding factors 2015a). Interestingly, EDI-2 total scores were also significantly higher in
not considered in the present study. the high anxiety group, but a significant correlation with
While the present study detected a positive correlation of NUCB2/ NUCB2/nesfatin-1 was lacking (Hofmann et al., 2015a). As anorexia
nesfatin-1 plasma levels with BMI in our male population, conversely nervosa is often accompanied with anxiety disorder (Godart et al., 2002)
also a negative correlation of peripheral NUCB2/nesfatin-1 and BMI was and the severity of this disease aggravates with comorbid generalized
reported in men with normal weight under fasting condition (Tsuchiya anxiety disorder (Riquin et al., 2021), the positive association of eating
et al., 2010). Interestingly, a negative correlation of NUCB2/nesfatin-1 disorder symptoms and the extent of anxiety is comprehensible. In
with BMI was reported in girls with obesity with a lacking association concordance with these previous results (Hofmann et al., 2015a), a
in boys (de Dios et al., 2019). Therefore, it might be assumed that due to relation between NUCB2/nesfatin-1 and eating behavior in patients
its pleiotropic properties, NUCB2/nesfatin-1 is also affected by age. For with anorexia nervosa could not be observed in the present study.
example, in animal studies NUCB2 mRNA expression in the hypothala­ Whether nesfatin-1 is predominantly involved in the regulation or
mus and pituitary alternates depending on sexual maturation with the maintenance of anxiety and to a minor degree mediating pathological
highest expression in pubertal and adult male rats or the testicular eating behavior in patients with anorexia nervosa should be further

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E. Weibert et al. Psychoneuroendocrinology 143 (2022) 105842

investigated. Funding
Notably, the strength of the study is the inclusion of a mixed-sex
study population with a wide range of BMI, providing new insight in This work was supported by the German Research Foundation
the involvement of nesfatin-1 in eating behavior with a focus on sex- (Germany) STE 1765/3-2 (A.S.) and Charité University Funding (Ger­
specific regulation. Nonetheless, several limitations should be consid­ many) UFF 89-441-176 (A.S., T.H.).
ered when interpreting the results of the present work. First, the group
sizes are different. Especially in the control group and in patients with CRediT authorship contribution statement
anorexia nervosa, male subjects are markedly underrepresented in
comparison to females. This resulted in a small sample size, limiting the Conceptualization – T.H. and A.S.; collection and processing of the
statistical power, and thus prohibiting a generalization of our findings. It data – E.W.; analysis and interpretation of the data -– E.W. T.H. and A.S.;
is to note that eating disorders like anorexia nervosa are rare diseases. literature research – E.W. and T.H.; writing/original draft preparation –
The lifetime prevalence of anorexia nervosa depending on the diagnostic E.W.; visualization – E.W., T.H. and A.S.; writing/review and editing – T.
criteria [Diagnostic and Statistical Manual of Mental Disorders – DSM IV H. and A.S.; supervision – T.H. and A.S. All authors have read and agreed
vs. 5 (Serrano-Troncoso et al., 2017)] ranges between 0.3 % and 4.3% in to the published version of the manuscript.
women (Smink et al., 2012). In males, the lifetime prevalence is even
presented as up to 0.3 % (Smink et al., 2012). In general, the ratio of References
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and obesity. Eat. Weight Disord. 25, 1333–1345. https://doi.org/10.1007/s40519-
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