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Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety., (© 2024. The Author(s).)

Functional gastrointestinal disorders are frequent diseases often associated with a pronounced burden reflected in a greatly reduced quality of life. Patients are seeking medical help but may be perceived as demanding and challenging. For successful diagnosis and treatment of these patients, a good doctor-patient communication is key. However, so far, only few studies focus on the physicians' perspective of the doctor-patient communication. The present study cross-sectionally investigated 520 physicians using the validated difficult doctor-patient relationship questionnaire and the treatment satisfaction questionnaire from the physician's perspective along with several ad hoc questions. Data from 5,354 physician-patient conversations (one conversation per patient) was included. Physicians participating in this study mostly suspected stress-related burdens as the cause of functional gastrointestinal disorders (65.4%), while patients rather suspected food (55.4%) or other somatic causes (43.6%). The physician-patient relationship was rated just below the threshold for difficult interactions (cut-off ≥30, mean ± SD in the current sample: 28.6 ± 9.6) with 49.1% of physicians reaching a score of ≥30. Although physicians overall felt confident in the doctor-patient communication even in difficult conversations (61.9%), only 33.1% reported to have enough time for these patients and only 5.6% felt sufficiently compensated for discussions with patients with functional gastrointestinal disorders. Therefore, education of physicians on functional gastrointestinal disorders, training of physicians in physician-patient communication as well as an improved reimbursement of speaking medicine should help to further improve care for these patients and also treatment satisfaction on both the side of the patients as well as the physicians., Competing Interests: MG-S was employed by Helios Klinik Rottweil and received payments for scientific lectures from Dr. Falk Pharma, Dr. Willmar Schwabe GmbH & Co. KG, Medical Tribune, Medice, Microbiotica and Yakult, as well as fees for consulting services from Medice and Yakult. UP and PB are employees of Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany. The study was not related to any product and is free of commercial interests. SZ receives loyalties from Frontiers and Thieme Verlag. AS worked as a consultant for a & r Berlin, Boehringer-Ingelheim and Takeda and received payments for scientific presentations from Bayer, Dr. Willmar Schwabe GmbH & Co. KG., Medice, Medical Tribune and Microbiotica., (Copyright © 2023 Goebel-Stengel, Paulsen, Bennerscheidt, Zipfel and Stengel.)

Background: Gastrointestinal (GI) complaints are frequently observed in patients who suffer from anorexia nervosa (AN). These symptoms may hamper treatment and weight regain and are often perceived as the cause, not the consequence, of the disease. Since carbohydrate malabsorption also produces these symptoms, this might underly or contribute to these complaints. So far, the role of carbohydrate malabsorption (fructose malabsorption and lactose intolerance) in AN has not yet been investigated., Methods: For this case series, inpatients with AN of restrictive type ( n = 3), purging type ( n = 3), and atypical AN ( n = 1) conducted hydrogen breath tests with 25 g of fructose and 50 g of lactose to investigate carbohydrate malabsorption. Results were then analyzed in association with body mass index (BMI) and patient-reported outcomes (disordered eating, body image disturbances, anxiety, depressive symptoms, perceived stress, and GI complaints)., Results: Based on the hydrogen breath test results, three of the seven female patients were classified as lactose intolerant and one presented fructose malabsorption. Both hydrogen curves for fructose ( r = -0.632, p < 0.001) and lactose ( r = -0.704, p < 0.001) showed a negative correlation with BMI. No association was observed between hydrogen values and patient-reported outcomes., Conclusion: In patients with AN, GI symptoms caused by intolerance of common monosaccharides and disaccharides may be an underestimated burden and should be considered in the diagnosis and therapy of patients with AN. Due to the observed correlation with BMI, GI complaints after ingestion of fructose or lactose likely develop with decreasing body weight and are potentially reversible with weight regain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Buck, Goebel-Stengel, Mack, Zipfel and Stengel.)

During the pandemic, mental health was not only impaired in people after a SARS-CoV-2 infection, but also in people without previous infection. This is the first study on twins without prior SARS-CoV-2 infection to estimate the influence of genetic components and shared as well as individual environments on pandemic-associated fatigue. The study sample included 55 monozygotic and 45 dizygotic twin pairs. A total of 34.5% reported an increase in fatigue since the pandemic. A significant correlation was shown between the responses within monozygotic (χ2[1] = 11.14, p = 0.001) and dizygotic pairs (χ2[1] = 18.72, p < 0.001). In all pandemic-associated fatigue dimensions, individual environment (ranging from e2 = 0.64 to e2 = 0.84) and heritability (ranging from h2 = 0.32 to h2 = 1.04) seem to have the highest impact. The number of comorbidities significantly correlated with physical fatigue (Spearman’s ρ = 0.232, p < 0.001) and psychological impairment due to pandemic measures with the total fatigue score (Spearman’s ρ = 0.243, p < 0.001). However, calculated ANCOVAs with these significant correlations as covariates showed no significant influence on the mean values of the respective fatigue dimensions. Susceptibility to pandemic-associated fatigue may be genetically and environmentally determined, while intensity is also influenced by individual components. The prevalence of fatigue is high even in individuals without prior SARS-CoV-2 infection. Future mental health prevention and intervention programs should be implemented to alleviate the impact of the pandemic on the global population.

Background: The clinical presentation of COVID-19 shows a remarkably broad spectrum of symptoms. Although studies with adult twins on SARS-CoV-2 infection are rare so far, the fact that there is a genetic component associated with the highly variable clinical outcomes of COVID-19 has already been highlighted in recent studies investigating potential candidate genes and polymorphisms. This is the first study of adult monozygotic (MZ) and dizygotic (DZ) twins concordantly affected by SARS-CoV-2 infection to estimate variances explained by genetic, shared, and individual environmental components of both somatic and psychological symptoms following SARS-CoV-2 infection., Materials and Methods: Data were collected from 10 adult twin pairs (5 MZ, 5 DZ) in which both twins already had a SARS-CoV-2 infection. A self-designed questionnaire, the Barthel Index, and the Multidimensional Fatigue Inventory (MFI) were used to assess various symptoms and health status following SARS-CoV-2 infection. Intra-class correlations were calculated, and the Falconer formula was used to quantify and differentiate the percentages of genetic influences as well as common environment and personal experiences on the examined traits. In addition, potential factors influencing symptom burden were examined and discussed., Results: We found high estimated heritability for mental impairment after SARS-CoV-2 infection ( h 2 = 1.158) and for general fatigue ( h 2 = 1.258). For symptom burden, reduced activity, and reduced motivation the individual environment appears to have the strongest influence. Other fatigue symptoms are influenced by genetic effects which range between 42.8 and 69.4%., Conclusion: Both genetics and individual environment play a role in health status after SARS-CoV-2 infection-mental status could be influenced primarily by genetic make-up, whereas for symptom burden and certain fatigue dimensions, non-shared environment could play a more critical role. Possible individual factors influencing the course of the disease were identified. However, gene-environment interactions may still be a source of differences between twins, and the search for candidate genes remains crucial on the road to personalized medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rupp, Weimer, Goebel-Stengel, Enck, Zipfel and Stengel.)

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT 3 receptor family. 5-HT 3 Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT 3 R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D., (© 2022. The Author(s).)

Background: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit ( HTR3 ) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS)., Aim: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS., Methods: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays., Results: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model ( F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score ( F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT 3 AC variant receptors., Conclusion: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS., Competing Interests: Conflict-of-interest statement: APC Microbiome Ireland has conducted studies in collaboration with several companies, including GSK, Pfizer, Cremo, Suntory, Wyeth, Mead Johnson, Nutricia, 4D Pharma, and DuPont. Dinan TG has been an invited speaker at meetings organized by Servier, Lundbeck, Janssen, and AstraZeneca and has received research funding from Mead Johnson, Cremo, Suntory Wellness, Nutricia, and 4D Pharma. Clarke G has been an invited speaker at meetings organized by Janssen and is receipt of research funding from Pharmavite. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

(1) Background: Booster vaccinations for SARS-CoV-2 convalescents are essential for achieving herd immunity. For the first time, this study examined the influencing factors of vaccination willingness among SARS-CoV-2 infected individuals and identified vaccination-hesitant subgroups. (2) Methods: Individuals with positive SARS-CoV-2 PCR results were recruited by telephone. They completed an online questionnaire during their home isolation in Germany. This questionnaire assessed the vaccination willingness and its influencing factors. (3) Results: 224 home-isolated individuals with acute SARS-CoV-2 infection were included in the study. Vaccination willingness of home-isolated SARS-CoV-2 infected individuals with asymptomatic or moderate course was 54%. The following factors were associated with significantly lower vaccination willingness: younger age, foreign nationality, low income, low trust in vaccination effectiveness, fear of negative vaccination effects, low trust in the governmental pandemic management, low subjective informativeness about SARS-CoV-2, support of conspiracy theories. (4) Conclusions: The vaccination willingness of home-isolated SARS-CoV-2 infected individuals with asymptomatic or moderate symptomatic course was low. Motivational vaccination campaigns should be adapted to individuals with acute SARS-CoV-2 infection and consider the vaccination-hesitant groups. Vaccination education should be demand-driven, low-threshold, begin during the acute infection phase, and be guided for example by the established 5C model ("confidence, complacency, constraints, calculation, collective responsibility").

Due to phoenixin's role in restraint stress and glucocorticoid stress, as well as its recently shown effects on the inflammasome, we aimed to investigate the effects of lipopolysaccharide (LPS)-induced inflammatory stress on the activity of brain nuclei-expressing phoenixin. Male Sprague Dawley rats ( n = 6/group) were intraperitoneally injected with either LPS or control (saline). Brains were processed for c-Fos and phoenixin immunohistochemistry and the resulting slides were evaluated using ImageJ software. c-Fos was counted and phoenixin was evaluated using densitometry. LPS stress significantly increased c-Fos expression in the central amygdaloid nucleus (CeM, 7.2-fold), supraoptic nucleus (SON, 34.8 ± 17.3 vs. 0.0 ± 0.0), arcuate nucleus (Arc, 4.9-fold), raphe pallidus (RPa, 5.1-fold), bed nucleus of the stria terminalis (BSt, 5.9-fold), dorsal motor nucleus of the vagus nerve (DMN, 89-fold), and medial part of the nucleus of the solitary tract (mNTS, 121-fold) compared to the control-injected group ( p < 0.05). Phoenixin expression also significantly increased in the CeM (1.2-fold), SON (1.5-fold), RPa (1.3-fold), DMN (1.3-fold), and mNTS (1.9-fold, p < 0.05), leading to a positive correlation between c-Fos and phoenixin in the RPa, BSt, and mNTS ( p < 0.05). In conclusion, LPS stress induces a significant increase in activity in phoenixin immunoreactive brain nuclei that is distinctively different from restraint stress.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Several studies have implied a role of brain-derived neurotrophic factor (BDNF) in abdominal pain modulation in irritable bowel syndrome (IBS). The aim of this study was to establish BDNF protein expression in human colonic biopsies and to show variation in IBS compared to controls. BDNF protein and mRNA levels were correlated with IBS symptom severity based on the IBS-symptom severity score (IBS-SSS). Biopsies from the descending colon and IBS-SSS were obtained from 10 controls and 20 IBS patients. Total protein of biopsies was extracted and assessed by ELISA and Western Blot. Total mRNA was extracted and gene expression measured by nCounter analysis. In IBS patients, symptom severity scores ranged from 124 to 486 (mean ± sem: 314.2 ± 21.2, >300 represents severe IBS) while controls ranged from 0 to 72 (mean ± sem: 27.7 ± 9.0, <75 represents healthy subjects, p < 0.001). IBS patients reported significantly more food malabsorption, former abdominal surgery and psychiatric comorbidities. BDNF protein was present in all samples and did not differ between IBS and controls or sex. Subgroup analysis showed that female IBS patients expressed significantly more BDNF mRNA compared to male patients ( p < 0.05) and male IBS-D patients had higher IBS symptom severity scores and lower BDNF mRNA and protein levels compared to male controls ( p < 0.05). Scatter plot showed a significant negative correlation between IBS-SSS and BDNF mRNA levels in the cohort of male IBS-D patients and their male controls ( p < 0.05). We detected a high proportion of gastrointestinal surgery in IBS patients and confirmed food intolerances and psychiatric diseases as common comorbidities. Although in a small sample, we demonstrated that BDNF is detectable in human descending colon, with higher BDNF mRNA levels in female IBS patients compared to males and lower mRNA and protein levels in male IBS-D patients compared to male controls. Further research should be directed toward subgroups of IBS since their etiologies might be different., Competing Interests: AS is consultant for a & r Berlin, Boehringer-Ingelheim, Takeda and Dr. Willmar Schwabe GmbH. MG-S is consultant for Dr. Willmar Schwabe GmbH and Yakult. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Konturek, Martinez, Niesler, van der Voort, Mönnikes, Stengel and Goebel-Stengel.)

Nesfatin-1 is a well-established anorexigenic peptide. Recent studies indicated an association between nesfatin-1 and anxiety/depression-like behavior. However, it is unclear whether this effect is retained in obesity. The aim was to investigate the effect of nesfatin-1 30-59 -the active core of nesfatin-1-on anxiety and depression-like behavior in normal weight (NW) and diet-induced (DIO) obese rats. Male rats were intracerebroventricularly (ICV) cannulated and received nesfatin-1 30-59 (0.1, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. Nesfatin-1 30-59 at a dose of 0.3 nmol reduced sucrose consumption in the sucrose preference test in NW rats compared to vehicle (⁻33%, p < 0.05), indicating depression-like/anhedonic behavior. This dose was used for all following experiments. Nesfatin-1 30-59 also reduced cookie intake during the novelty-induced hypophagia test (-62%, p < 0.05). Moreover, nesfatin-1 30-59 reduced the number of entries into the center zone in the open field test (-45%, p < 0.01) and the visits of open arms in the elevated zero maze test (-39%, p < 0.01) in NW rats indicating anxiety. Interestingly, DIO rats showed no behavioral alterations after the injection of nesfatin-1 30-59 ( p > 0.05). These results indicate an implication of nesfatin-1 30-59 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.

Treatment of eating disorders like obesity or anorexia is challenging. Options are limited and new approaches desired. An interesting approach is the application of deep brain stimulation (DBS). The nucleus accumbens (NAcc) is part of the food reward system. A pilot study reported that DBS of the NAcc shell modulates food intake and body weight in rats. Underlying mechanisms such as the food intake microstructure are unknown so far. Normal weight female Sprague-Dawley rats were equipped with a custom-made DBS electrode placed unilaterally in the NAcc shell. Biphasic stimulation was performed for seven days. Body weight and food intake including the microstructure were assessed over the experimental period. Behavior was monitored manually. DBS tended to increase body weight gain (28.1 ± 5.4 g) compared to sham-stimulated controls (16.7 ± 3.4, P = 0.05) without affecting daily food intake (P > 0.05). Further analyses showed that light phase food intake was stimulated, whereas dark phase food intake was decreased in the DBS group (P < 0.05). During the light phase bout frequency (+50%), bout duration (+64%), meal duration (+71%) and overall time spent in meals (+92%) were increased in DBS rats (P < 0.05), while during the dark phase no alterations were observed (P > 0.05). Behavior did not show differences regarding overall eating and drinking behavior (including food/water approach), grooming or locomotion (P > 0.05). Summarized, although overall food intake was not changed by DBS, light phase food intake was stimulated likely via a reduction of satiation.

Background: Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex., Methods: Male and female CRF-OE mice and WT littermates (4-6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals., Results: Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF-OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females., Conclusions: These data indicate that CRF-OE mice have abnormal basal and fasting circulating hormones and hypothalamic feeding-related signals. CRF-OE also abolishes the sex difference in body weight, abdominal fat, and fasting-induced feeding and changes in plasma levels of leptin and acyl ghrelin.

Anorexia nervosa (AN) is accompanied by severe somatic and psychosocial complications. However, the underlying pathogenesis is poorly understood, treatment is challenging and often hampered by high relapse. Therefore, more basic research is needed to better understand the disease. Since hyperactivity often plays a role in AN, we characterized an animal model to mimic AN using restricted feeding and hyperactivity. Female Sprague-Dawley rats were divided into four groups: no activity/ ad libitum feeding ( ad libitum , AL, n = 9), activity/ ad libitum feeding (activity, AC, n = 9), no activity/restricted feeding (RF, n = 12) and activity/restricted feeding (activity-based anorexia, ABA, n = 11). During the first week all rats were fed ad libitum , ABA and AC had access to a running wheel for 24 h/day. From week two ABA and RF only had access to food from 9:00 to 10:30 a.m. Body weight was assessed daily, activity and food intake monitored electronically, brain activation assessed using Fos immunohistochemistry at the end of the experiment. While during the first week no body weight differences were observed ( p > 0.05), after food restriction RF rats showed a body weight decrease: -13% vs. day eight ( p < 0.001) and vs. AC (-22%, p < 0.001) and AL (-26%, p < 0.001) that gained body weight (+10% and +13%, respectively; p < 0.001). ABA showed an additional body weight loss (-9%) compared to RF ( p < 0.001) reaching a body weight loss of -22% during the 2-week restricted feeding period ( p < 0.001). Food intake was greatly reduced in RF (-38%) and ABA (-41%) compared to AL ( p < 0.001). Interestingly, no difference in 1.5-h food intake microstructure was observed between RF and ABA ( p > 0.05). Similarly, the daily physical activity was not different between AC and ABA ( p > 0.05). The investigation of Fos expression in the brain showed neuronal activation in several brain nuclei such as the supraoptic nucleus, arcuate nucleus, locus coeruleus and nucleus of the solitary tract of ABA compared to AL rats. In conclusion, ABA combining physical activity and restricted feeding likely represents a suited animal model for AN to study pathophysiological alterations and pharmacological treatment options. Nonetheless, cautious interpretation of the data is necessary since rats do not voluntarily reduce their body weight as observed in human AN.

Background: Nucleobindin2 (NUCB2)/nesfatin-1 plays a well-established role in homeostatic functions associated with food intake and stress integration., Aim: This review focusses on NUCB2/nesfatin-1's central effects on gastrointestinal functions and will summarize the effects on food intake, motility and secretion with focus on the upper gastrointestinal tract., Results: We will highlight the stressors that influence brain NUCB2/nesfatin-1 expression and discuss functional implications. In addition to traditional acute psychological and physical stressors such as restraint stress and abdominal surgery we will look at immunological, visceral and metabolic stressors as well as a chronic combination stress model that have been shown to affect NUCB2/nesfatin-1 signaling and describe associated functional consequences.

Nesfatin-1 is well-established to induce an anorexigenic effect. Recently, nesfatin-130-59, was identified as active core of full length nesfatin-11-82 in mice, while its role in rats remains unclear. Therefore, we investigated the effects of nesfatin-130-59 injected intracerebroventricularly (icv) on the food intake microstructure in rats. To assess whether the effect was also mediated peripherally we injected nesfatin-130-59 intraperitoneally (ip). Since obesity affects the signaling of various food intake-regulatory peptides we investigated the effects of nesfatin-130-59 under conditions of diet-induced obesity (DIO). Male Sprague-Dawley rats fed ad libitum with standard diet were icv cannulated and injected with vehicle (5 μl ddH2O) or nesfatin-130-59 at 0.37, 1.1, and 3.3 μg (0.1, 0.3, 0.9 nmol/rat) and the food intake microstructure assessed using a food intake monitoring system. Next, naïve rats were injected ip with vehicle (300 μl saline) or nesfatin-130-59 (8.1, 24.3, 72.9 nmol/kg). Lastly, rats were fed a high fat diet for 10 weeks and those developing DIO were icv cannulated. Nesfatin-1 (0.9 nmol/rat) or vehicle (5 μl ddH2O) was injected icv and the food intake microstructure assessed. In rats fed standard diet, nesfatin-130-59 caused a dose-dependent reduction of dark phase food intake reaching significance at 0.9 nmol/rat in the period of 4-8 h post injection (-29%) with the strongest reduction during the fifth hour (-75%), an effect detectable for 24 h (-12%, p < 0.05 vs. vehicle). The anorexigenic effect of nesfatin-130-59 was due to a reduction in meal size (-44%, p < 0.05), while meal frequency was not altered compared to vehicle. In contrast to icv injection, nesfatin-130-59 injected ip in up to 30-fold higher doses did not alter food intake. In DIO rats fed high fat diet, nesfatin-130-59 injected icv reduced food intake in the third hour post injection (-71%), an effect due to a reduced meal frequency (-27%, p < 0.05), while meal size was not altered. Taken together, nesfatin-130-59 is the active core of nesfatin-11-82 and acts centrally to reduce food intake in rats. The anorexigenic effect depends on the metabolic condition with increased satiation (reduction in meal size) under normal weight conditions, while in DIO rats satiety (reduction in meal frequency) is induced.

The ghrelin acylating enzyme ghrelin-O-acyltransferase (GOAT) was recently identified and implicated in several biological functions. However, the effects on food intake warrant further investigation. While several genetic GOAT mouse models showed normal food intake, acute blockade using a GOAT inhibitor resulted in reduced food intake. The underlying food intake microstructure remains to be established. In the present study we used an automated feeding monitoring system to assess food intake and the food intake microstructure. First, we validated the basal food intake and feeding behavior in rats using the automated monitoring system. Afterwards, we assessed the food intake microstructure following intraperitoneal injection of the GOAT inhibitor, GO-CoA-Tat (32, 96 and 288 μg/kg) in freely fed male Sprague-Dawley rats. Rats showed a rapid habituation to the automated food intake monitoring system and food intake levels were similar compared to manual monitoring (P = 0.43). Rats housed under these conditions showed a physiological behavioral satiety sequence. Injection of the GOAT inhibitor resulted in a dose-dependent reduction of food intake with a maximum effect observed after 96 mg/kg (-27%, P = 0.03) compared to vehicle. This effect was delayed in onset as the first meal was not altered and lasted for a period of 2 h. Analysis of the food intake microstructure showed that the anorexigenic effect was due to a reduction of meal frequency (-15%, P = 0.04), whereas meal size (P = 0.29) was not altered compared to vehicle. In summary, pharmacological blockade of GOAT reduces dark phase food intake by an increase of satiety while satiation is not affected.

Bile acids may be involved in the regulation of food intake and energy metabolism. The aim of the study was to investigate the association of plasma bile acids with body mass index (BMI) and the possible involvement of circulating bile acids in the modulation of physical activity and eating behavior. Blood was obtained in a group of hospitalized patients with normal weight (BMI 18.5-25 kg/m(2)), underweight (anorexia nervosa, BMI < 17.5 kg/m(2)) and overweight (obesity with BMI 30-40, 40-50 and >50 kg/m(2), n = 14-15/group) and plasma bile acid concentrations assessed. Physical activity and plasma bile acids were measured in a group of patients with anorexia nervosa (BMI 14.6 ± 0.3 kg/m(2), n = 43). Lastly, in a population of obese patients (BMI 48.5 ± 0.9 kg/m(2), n = 85), psychometric parameters related to disordered eating and plasma bile acids were assessed. Plasma bile acids showed a positive correlation with BMI (r = 0.26, p = 0.03) in the population of patients with broad range of BMI (9-85 kg/m(2), n = 74). No associations were observed between plasma bile acids and different parameters of physical activity in anorexic patients (p > 0.05). Plasma bile acids were negatively correlated with cognitive restraint of eating (r = -0.30, p = 0.008), while no associations were observed with other psychometric eating behavior-related parameters (p > 0.05) in obese patients. In conclusion, these data may point toward a role of bile acids in the regulation of body weight. Since plasma bile acids are negatively correlated with the cognitive restraint of eating in obese patients, this may represent a compensatory adaptation to prevent further overeating.

Background/aims: Carbohydrate malabsorption is frequent in patients with functional gastrointestinal disorders and in healthy volunteers and can cause gastrointestinal symptoms mimicking irritable bowel syndrome (IBS). The aim of this study was to investigate the prevalence of symptomatic lactose and fructose malabsorption in a large population of patients with IBS-like symptoms based on Rome II criteria., Methods: Patients with unclear abdominal discomfort (n = 2,390) underwent lactose (50 g) and fructose (50 g) hydrogen (H2) breath tests and depending on the results further testing with 25 g fructose or 50 g glucose, or upper endoscopy with duodenal biopsies. Additionally, this population was investigated regarding the prevalence of small intestinal bacterial overgrowth (SIBO) based on glucose breath test and celiac disease., Results: Of the 2,390 patients with IBS-like symptoms, 848 (35%) were symptomatic lactose malabsorbers and 1,531 (64%) sympto-matic fructose malabsorbers. A combined symptomatic carbohydrate malabsorption was found in 587 (25%) patients. Severe fructose malabsorbers (pathologic 25 g fructose test) exhaled significantly higher H2 concentrations in the 50 g test than pa-tients with negative 25 g fructose test (P < 0.001). Out of 460/659 patients with early significant H2 increase in the lactose and fructose test who underwent a glucose breath test, 88 patients had positive results indicative of SIBO and they were sig-nificantly older than patients with negative test result (P < 0.01). Celiac disease was found in 1/161 patients by upper endoscopy., Conclusions: Carbohydrate malabsorption is a frequent but underestimated condition in patients with IBS-like symptoms although diagnosis can be easily confirmed by H2 breath testing.

Tail pinch stimulates food intake in rats. We investigated brain mechanisms of this response and the influence of repeated exposure. Sprague-Dawley rats received acute (5 min) or repeated (5 min/day for 14 days) tail pinch using a padded clip. Acute tail pinch increased 5-min food intake compared with control (0.92 ± 0.2 vs. 0.03 ± 0.01 g, P < 0.01). This response was inhibited by 76% by intracerebroventricular injection of BIBP-3226, a neuropeptide Y1 (NPY1) receptor antagonist, increased by 48% by astressin-B, a corticotropin-releasing factor (CRF) receptor antagonist, and not modified by S-406-028, a somatostatin subtype 2 antagonist. After the 5-min tail pinch without food, blood glucose rose by 21% (P < 0.01) while changes in plasma acyl ghrelin (+41%) and adrenocorticotropic hormone (+37%) were not significant. Two tail pinches (45 min apart) activate pontine and hindbrain catecholaminergic and hypothalamic paraventricular CRF neurons. After 14 days of repeated tail pinch, the 5-min orexigenic response was not significantly different from days 2 to 11 but reduced by 50% thereafter (P < 0.001). Simultaneously, the 5-min fecal pellet output increased during the last 5 days compared with the first 5 days (+58%, P < 0.05). At day 14, the body weight gain was reduced by 22%, with a 99% inhibition of fat gain and a 25% reduction in lean mass (P < 0.05). The orexigenic response to acute 5-min tail pinch is likely to involve the activation of brain NPY1 signaling, whereas that of CRF tends to dampen the acute response and may contribute to increased defecation and decreased body weight gain induced by repeated tail pinch.

Obesity is an increasing health problem. Because drug treatments are limited, diets remain popular. High-protein diets (HPD) reduce body weight (BW), although the mechanisms are unclear. We investigated physiological mechanisms altered by switching diet induced obesity (DIO) rats from Western-type diet (WTD) to HPD. Male rats were fed standard (SD) or WTD (45% calories from fat). After developing DIO (50% of rats), they were switched to SD (15% calories from protein) or HPD (52% calories from protein) for up to 4 weeks. Food intake (FI), BW, body composition, glucose tolerance, insulin sensitivity, and intestinal hormone plasma levels were monitored. Rats fed WTD showed an increased FI and had a 25% greater BW gain after 9 wk compared with SD (P < 0.05). Diet-induced obese rats switched from WTD to HPD reduced daily FI by 30% on day 1, which lasted to day 9 (-9%) and decreased BW during the 2-wk period compared with SD/SD (P < 0.05). During these 2 wk, WTD/HPD rats lost 72% more fat mass than WTD/SD (P < 0.05), whereas lean mass was unaltered. WTD/HPD rats had lower blood glucose than WTD/SD at 30 min postglucose gavage (P < 0.05). The increase of pancreatic polypeptide and peptide YY during the 2-h dark-phase feeding was higher in WTD/HPD compared with WTD/SD (P < 0.05). These data indicate that HPD reduces BW in WTD rats, which may be related to decreased FI and the selective reduction of fat mass accompanied by improved glucose tolerance, suggesting relevant benefits of HPD in the treatment of obesity.

Various molecular forms of CCK reduce food intake in rats. Although CCK-8 is the most studied form, we reported that CCK-58 is the only detectable endocrine peptide form in rats. We investigated the dark-phase rat chow intake pattern following injection of CCK-8 and CCK-58. Ad libitum-fed male Sprague-Dawley rats were intraperitoneally injected with CCK-8, CCK-58 (0.6, 1.8, and 5.2 nmol/kg), or vehicle. Food intake pattern was assessed during the dark phase using an automated weighing system that allowed continuous undisturbed monitoring of physiological eating behavior. Both CCK-8 and CCK-58 dose dependently reduced 1-h, dark-phase food intake, with an equimolar dose of 1.8 nmol being similarly effective (-49% and -44%). CCK-58 increased the latency to the first meal, whereas CCK-8 did not. The intermeal interval was reduced after CCK-8 (1.8 nmol/kg, -41%) but not after CCK-58. At this dose, CCK-8 increased the satiety ratio by 80% and CCK-58 by 160%, respectively, compared with vehicle. When behavior was assessed manually, CCK-8 reduced locomotor activity (-31%), whereas grooming behavior was increased (+59%). CCK-58 affected neither grooming nor locomotor activity. In conclusion, reduction of food intake by CCK-8 and CCK-58 is achieved by differential modulation of food intake microstructure and behavior. These data highlight the importance of studying the molecular forms of peptides that exist in vivo in tissue and circulation of the animal being studied.

Clinical studies are evaluating the efficacy of synthetic ghrelin agonists in postoperative ileus management. However, the control of ghrelin secretion under conditions of postoperative gastric ileus is largely unknown. Peripheral somatostatin inhibits ghrelin secretion in animals and humans. We investigated the time course of ghrelin changes postsurgery in fasted rats and whether somatostatin receptor subtype 2 (sst(2)) signaling is involved. Abdominal surgery (laparotomy and 1-min cecal palpation) induced a rapid and long-lasting decrease in plasma acyl ghrelin levels as shown by the 64, 67, and 59% reduction at 0.5, 2, and 5 h postsurgery, respectively, compared with sham (anesthesia alone for 10 min, P < 0.05). Levels were partly recovered at 7 h and fully restored at 24 h. The percentage of acyl ghrelin reduction was significantly higher than that of desacyl ghrelin at 2 h postsurgery and not at any other time point. This was associated with a 48 and 23% decrease in gastric and plasma ghrelin-O-acyltransferase protein concentrations, respectively (P < 0.001). Ghrelin-positive cells in the oxyntic mucosa expressed sst(2a) receptor and the sst(2) agonist S-346-011 inhibited fasting acyl ghrelin levels by 64 and 77% at 0.5 and 2 h, respectively. The sst(2) antagonist S-406-028 prevented the abdominal surgery-induced decreased circulating acyl ghrelin but not the delayed gastric emptying assessed 0.5 h postinjection. These data show that activation of sst(2) receptor located on gastric X/A-like cells plays a key role in the rapid inhibition of circulating acyl ghrelin induced by abdominal surgery while not being primarily involved in the early phase of postoperative gastric ileus.