105 research outputs found
Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones
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 (4â6 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 femaleâ>âmale.
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
Assessment of Physical Activity Patterns in Adolescent Patients With Anorexia Nervosa and Their Effect on Weight Gain
(1) Background: Altered physical activity (PA) affects weight recovery in anorexia nervosa (AN) patients. The study aimed to objectively characterize PA patterns and their effect on weight trajectory in adolescent AN patients.
(2) Methods: PA was assessed in 47 patients on admission to inpatient treatment, in n = 25 of these patients again 4 weeks after discharge (follow-up, FU), as well as in 20 adolescent healthy controls using the Sense Wearâą armband. The following PA categories were defined by metabolic equivalent (MET) ranges: sedentary behavior (SB), light (LPA), moderate (MPA), vigorous (VPA), and high-level PA (HLPA= MPA + VPA).
(3) Results: LPA on admission was significantly higher in AN patients than in controls (103 vs. 55 min/d, p < 0.001), and LPA in AN decreased over time to 90 min/d (p = 0.006). Patients with higher admission LPA (n = 12) still had elevated LPA at FU (p = 0.003). High admission LPA was associated with a higher inpatient BMI percentage gain (ÎBMI%; 18.2% ± 10.0% vs. 12.0% ± 9.7%, p = 0.037) but with a loss of ÎBMI% at FU (-2.3% ± 3.6% vs. 0.8% ± 3.6%, p = 0.045). HLPA at baseline was associated with a lower inpatient ÎBMI% (p = 0.045).
(4) Conclusion: Elevated LPA in AN patients decreased after inpatient treatment, and PA patterns had an impact on weight trajectory
Activity-Based Anorexia Reduces Body Weight without Inducing a Separate Food Intake Microstructure or Activity Phenotype in Female RatsâMediation via an Activation of Distinct Brain Nuclei
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 24h/d. From week two ABA and RF only had access to food from 9:00-10:30 am. 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 (p0.05). 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
Nesfatin-130â59 Injected Intracerebroventricularly Differentially Affects Food Intake Microstructure in Rats Under Normal Weight and Diet-Induced Obese Conditions
Nesfatin-1 is well-established to induce an anorexigenic effect. Recently,
nesfatin-130â59, was identified as active core of full length nesfatin-11â82
in mice, while its role in rats remains unclear. Therefore, we investigated
the effects of nesfatin-130â59 injected intracerebroventricularly (icv) on the
food intake microstructure in rats. To assess whether the effect was also
mediated peripherally we injected nesfatin-130â59 intraperitoneally (ip).
Since obesity affects the signaling of various food intake-regulatory peptides
we investigated the effects of nesfatin-130â59 under conditions of diet-
induced obesity (DIO). Male SpragueâDawley rats fed ad libitum with standard
diet were icv cannulated and injected with vehicle (5 ÎŒl ddH2O) or
nesfatin-130â59 at 0.37, 1.1, and 3.3 ÎŒg (0.1, 0.3, 0.9 nmol/rat) and the food
intake microstructure assessed using a food intake monitoring system. Next,
naĂŻve rats were injected ip with vehicle (300 ÎŒl saline) or nesfatin-130â59
(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 ÎŒl ddH2O) was injected icv and the food intake microstructure
assessed. In rats fed standard diet, nesfatin-130â59 caused a dose-dependent
reduction of dark phase food intake reaching significance at 0.9 nmol/rat in
the period of 4â8 h post injection (â29%) with the strongest reduction during
the fifth hour (â75%), an effect detectable for 24 h (â12%, p < 0.05 vs.
vehicle). The anorexigenic effect of nesfatin-130â59 was due to a reduction in
meal size (â44%, p < 0.05), while meal frequency was not altered compared to
vehicle. In contrast to icv injection, nesfatin-130â59 injected ip in up to
30-fold higher doses did not alter food intake. In DIO rats fed high fat diet,
nesfatin-130â59 injected icv reduced food intake in the third hour post
injection (â71%), an effect due to a reduced meal frequency (â27%, p < 0.05),
while meal size was not altered. Taken together, nesfatin-130â59 is the active
core of nesfatin-11â82 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
Nesfatin-1(30-59) injected intracerebroventricularly increases anxiety, depression-like behavior, and anhedonia in normal weight rats
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)âthe active core of nesfatin-1âon 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). 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
The serotonin receptor 3E variant is a risk factor for female IBS-D
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R 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
Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.
BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity â€2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029
The serotonin receptor 3E variant is a risk factor for female IBS-D
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT receptor family. 5-HT Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42Câ>âT (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76Gâ>âA (rs56109847â=ârs62625044) 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.*76Gâ>âA (rs56109847â=ârs62625044) to be associated with female IBS-D (ORâ=â1.58; 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 (pâ=â0.0187); more specifically, in those diagnosed with IBS-D (pâ=â0.0145). In conclusion, meta-analysis confirmed rs56109847â=ârs62625044 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. [Abstract copyright: © 2022. The Author(s).
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence âPrecision Medicine in Chronic In-flammationâ (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: âIdeasâ Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brainâgut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brainâgut interactions underlying IBS
Sucrose Preference and Novelty-Induced Hypophagia Tests in Rats using an Automated Food Intake Monitoring System
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