Gastric electrical stimulation is safe during pregnancy and delivery: Results from a French cohort.

BACKGROUND: Gastric electrical stimulation (GES) is an effective therapy in medically refractory chronic nausea and vomiting. GES is assumed to be a contraindication for pregnancy. We examined the safety of GES during pregnancy and its clinical impact on vomiting symptoms. METHODS: A retrospective study was performed in two tertiary centers including all female patients of childbearing age implanted with GES. Patients without pregnancy while on GES were asked about their desire and concerns about pregnancy. Patients who were pregnant while on GES therapy were interviewed about the course of the pregnancy and labor, as well as the health of the children. KEY RESULTS: Among 91 patients implanted at childbearing age, 54 patients without pregnancy answered the questionnaire. Nine patients (16.7%) reported a desire for pregnancy and five patients (7.4%) reported worries about the safety of GES during pregnancy. Sixteen pregnancies were reported in 10 patients. All pregnancies ended in a live birth with premature birth in 12 pregnancies (75.0%). No health concern was currently noted in these children. No severe GES-related complications occurred during pregnancy with only pain at the implantation site reported during 3 pregnancies (18.8%). The severity and frequency of nausea and vomiting significantly increased during the first trimester (p = 0.04 and p = 0.005, respectively) and decreased after the delivery, becoming lower than before the pregnancy (p = 0.044 and p = 0.011, respectively). CONCLUSION & INFERENCES: Patients are concerned regarding pregnancy while being treated with GES. No serious maternal or fetal complications related to GES were noted in our cohort.

Locked Out: Phoenixin-14 Does Not Cross a Stem-Cell-Derived Blood-Brain Barrier Model.

Phoenixin-14 is a recently discovered peptide regulating appetite. Interestingly, it is expressed in the gastrointestinal tract; however, its supposed receptor, GPR173, is predominantly found in hypothalamic areas. To date, it is unknown how peripherally secreted phoenixin-14 is able to reach its centrally located receptor. To investigate whether phoenixin is able to pass the blood-brain barrier, we used an in vitro mono-culture blood-brain barrier (BBB) model consisting of brain capillary-like endothelial cells derived from human induced-pluripotent stem cells (hiPSC-BCECs). The passage of 1 nMol and 10 nMol of phoenixin-14 via the mono-culture was measured after 30, 60, 90, 120, 150, 180, 210, and 240 min using a commercial ELISA kit. The permeability coefficients (PC) of 1 nMol and 10 nMol phoenixin-14 were 0.021 ± 0.003 and 0.044 ± 0.013 µm/min, respectively. In comparison with the PC of solutes known to cross the BBB in vivo, those of phoenixin-14 in both concentrations are very low. Here, we show that phoenixin-14 alone is not able to cross the BBB, suggesting that the effects of peripherally secreted phoenixin-14 depend on a co-transport mechanism at the BBB in vivo. The mechanisms responsible for phoenixin-14's orexigenic property along the gut-brain axis warrant further research.

Abdominal surgery increases activity in several phoenixin immunoreactive nuclei.

BACKGROUND: Research on the peptide phoenixin has increased in recent years and greatly widened the known scope of its functions since its discovery in 2013. Involvement of phoenixin has since been shown in anxiety, food intake, reproduction as well as emotional and immunological stress. To further evaluate its involvement in stress reactions, this study aims to investigate the effects of abdominal surgery, a well-established physical stressor, on the activity of phoenixin-immunoreactive brain nuclei. METHODS: Male Sprague-Dawley rats (n = 6/group) were subjected to either an abdominal surgery stress protocol or a sham operation. Animals in the verum group were anesthetized, the abdominal cavity opened and the cecum palpated, followed by closing of the abdomen and recovery. Sham operated animals only received inhalation anesthesia and time for recovery. All animals were subsequently sacrificed and brains processed and evaluated for c-Fos activity as well as phoenixin density. RESULTS: Compared to control, abdominal surgery significantly increased c-Fos activity in the paraventricular nucleus (PVN, 6.4-fold, p < 0.001), the medial part of the nucleus of the solitary tract (mNTS, 3.8-fold, p < 0.001), raphe pallidus (RPa, 3.6-fold, p < 0.001), supraoptic nucleus (SON, 3.2-fold, p < 0.001), ventrolateral medulla (VLM, also called A1C1, 3.0-fold, p < 0.001), dorsal motor nucleus of vagus (DMN, 2.9-fold, p < 0.001), locus coeruleus (LC, 1.8-fold, p < 0.01) and Edinger-Westphal nucleus (EW, 1.6-fold, p < 0.05), while not significantly altering c-Fos activity in the amygdala (CeM, 1.3-fold, p > 0.05). Phoenixin immunoreactivity was not significantly affected by abdominal surgery (p > 0.05). CONCLUSION: The observed abdominal surgery-related increase in activity in phoenixin immunoreactive nuclei compared to sham surgery controls supports the hypothesis of an involvement of phoenixin in stress reactions. Interestingly, various psychological and physical stressors lead to specific changes in activity and immunoreactivity in phoenixin-containing nuclei, giving rise to a stressor-specific involvement of phoenixin.

Inflammatory Stress Induced by Intraperitoneal Injection of LPS Increases Phoenixin Expression and Activity in Distinct Rat Brain Nuclei.

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.

The Role of the Gastric Hormones Ghrelin and Nesfatin-1 in Reproduction.

Ghrelin and nesfatin-1 are enteroendocrine peptide hormones expressed in rat X/A-like and human P/D1cells of the gastric mucosa. Besides their effect on food intake, both peptides are also implicated in various other physiological systems. One of these is the reproductive system. This present review illustrates the distribution of ghrelin and nesfatin-1 along the hypothalamus-pituitary-gonadal (HPG) axis, their modulation by reproductive hormones, and effects on reproductive functions as well as highlighting gaps in current knowledge to foster further research.

Irritable bowel syndrome and functional dyspepsia in patients with eating disorders - a systematic review.

OBJECTIVES: The prevalence of eating disorders is rising worldwide. The low body weight in anorexia nervosa as well as the increase in body mass index due to binge eating disorder are contributing to a strikingly high morbidity and mortality. In a similar pattern, the prevalence and burden of the disease of functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome is increasing. As gastrointestinal complaints are commonly reported by patients with eating disorders, the question arose whether there is a relationship between eating disorders and functional gastrointestinal disorders. METHODS: To address the need to better understand the interplay between eating disorders and functional gastrointestinal disorders as well as factors that might influence this connection, the data bases Medline, Web of Science and Embase were systematically searched. RESULTS: After removal of duplicates the search yielded 388 studies which were screened manually. As a result, 36 publications were selected for inclusion in this systematic review. CONCLUSION: The occurrence of functional gastrointestinal disorders like irritable bowel syndrome and functional dyspepsia in patients with eating disorders is considerably high and often associated with psychological, hormonal and functional alterations. In the future, further research addressing the underlying mechanisms accounting for this relationship is required.

Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake.

The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.

Effects of microbiome changes on endocrine ghrelin signaling - A systematic review.

The 28-amino acid peptide hormone ghrelin plays a unique role in the gut-brain axis: It is mainly produced peripherally in gastric X/A-like cells but stimulates food intake centrally via hypothalamic nuclei; thus, providing orexigenic communication between the gut and central food intake-regulatory centers. Another component of the gut-brain axis that gained increasing interest in recent years due to its ability to influence central signaling via metabolites is the gut microbiome. Interestingly, there is increasing evidence that changes in the microbiome are related to alterations in ghrelin expression, secretion, activation and signaling. Since ghrelin is supposedly implicated in the pathogenesis of obesity, changes in the microbiome were hypothesized to improve obesity via modulation of ghrelin abundance and receptor interaction. To shed more light on the association between the microbiome and ghrelin a systematic search of Medline, EMBASE and Web of science using the search term combination "microbiome AND ghrelin" was performed. As a result of the search, 42 publications were included into this systematic review, of which 30 publications reported preclinical and 12 manuscripts presented clinical data. In addition to a critical analysis of the present data, gaps in knowledge were highlighted in order to foster further research.

Sucrose Preference and Novelty-Induced Hypophagia Tests in Rats using an Automated Food Intake Monitoring System.

The prevalence and incidence of depressive disorders are rising worldwide, affecting about 322 million individuals, underlining the need for behavioral studies in animal models. In this protocol, to study depression-like and anhedonic behavior in rats, the established sucrose preference and novelty-induced hypophagia tests are combined with an automated food and liquid intake monitoring system. Prior to testing, in the sucrose preference paradigm, male rats are trained for at least 2 days to consume a sucrose solution in addition to tap water. During the test, rats are again exposed to water and sucrose solution. Consumption is registered every second by the automated system. The ratio of sucrose to total water intake (sucrose preference ratio) is a surrogate parameter for anhedonia. In the novelty-induced hypophagia test, male rats undergo a training period in which they are exposed to a palatable snack. During training, rodents show a stable baseline snack intake. On test day, the animals are transferred from home cages into a fresh, empty cage representing a novel unknown environment with access to the known palatable snack. The automated system records the total intake and its underlying microstructure (e.g., latency to approaching the snack), providing insight into anhedonic and anxious behaviors. The combination of these paradigms with an automated measuring system provides more detailed information, along with higher accuracy by reducing measuring errors. However, the tests use surrogate parameters and only depict depression and anhedonia in an indirect manner.

NUCB2/nesfatin-1 - Inhibitory effects on food intake, body weight and metabolism.

Since its discovery in 2006 by Oh-I and colleagues, NUCB2/nesfatin-1 encoded by nucleobindin-2 (NUCB2) has drawn sustained attention as reflected in over 500 publications. Among those, more than half focused on the alterations of food intake, body weight and metabolism (glucose, fat) induced by nesfatin-1 and/or NUCB2/nesfatin-1. In the current review we discuss the existing literature focusing on NUCB2/nesfatin-1's influence on food intake, body weight and glucose as well as fat metabolism and highlight gaps in knowledge.

Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges.

PURPOSE OF REVIEW: Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter ghrelin signaling. RECENT FINDINGS: Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, ghrelin-O-acyltransferase inhibitors as well as antagonists, and inverse agonists of the ghrelin receptor. PF-05190457 is the first inverse agonist of the ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined. Although various highly promising agents targeting ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of ghrelin antagonism on body weight especially under conditions of obesity.

Activity Based Anorexia as an Animal Model for Anorexia Nervosa-A Systematic Review.

Anorexia nervosa (AN) is a severe eating disorder affecting around 1 per 100 persons. However, the knowledge about its underlying pathophysiology is limited. To address the need for a better understanding of AN, an animal model was established early on in the late 1960's: the activity-based anorexia (ABA) model in which rats have access to a running wheel combined with restricted food access leading to self-starving/body weight loss and hyperactivity. Both symptoms, separately or combined, can also be found in patients with AN. The aim of this systematic review was to compile the current knowledge about this animal model as well as to address gaps in knowledge. Using the data bases of PubMed, Embase and Web of science 102 publications were identified meeting the search criteria. Here, we show that the ABA model mimics core features of human AN and has been characterized with regards to brain alterations, hormonal changes as well as adaptations of the immune system. Moreover, pharmacological interventions in ABA animals and new developments, such as a chronic adaptation of the ABA model, will be highlighted. The chronic model might be well suited to display AN characteristics but should be further characterized. Lastly, limitations of the model will be discussed.

Gastrointestinal alterations in anorexia nervosa - A systematic review.

OBJECTIVE: Anorexia nervosa (AN) is an eating disorder characterized by body schema disruptions, underweight (>15% reduction of the ideal body weight or a body mass index <17.5 kg/m2 ), self-induced weight reduction, and endocrine impairments. The three latter features greatly impact on most physiological functions including the cardiovascular, skeletal, reproductive, and the gastrointestinal system, which results in an increased mortality rate in affected individuals. Especially, gastrointestinal alterations are described as particularly bothersome by patients. METHODS: To address the need for a better understanding of the interplay between AN and the gastrointestinal (GI) tract, a systematic data search in the databases Medline, Embase, and PsycINFO was conducted. RESULTS: Over 1,235 studies were identified, out of these, 107 appropriate articles were selected and discussed in the present review. CONCLUSION: AN has large impact on GI alterations and symptoms; conversely, GI symptoms may also affect the manifestation and course of AN as discussed in the present review. Despite increasing data, several gaps in knowledge exist especially on the pathophysiology underlying the changes described.

The role of phoenixin in behavior and food intake.

The recently discovered peptide phoenixin was initially implicated in reproduction as a regulator of gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release from the pituitary. Subsequently, various functions of phoenixin have been demonstrated including mediation of itching sensation, stimulation of vasopressin secretion, stimulation of white adipogenesis and hypothalamic nutrient sensing. Subsequently, additional actions of phoenixin have been described, namely effects on behavior. A systematic search of four data bases was performed and original articles selected accordingly. The present systematic review will present the current knowledge on the effects of phoenixin on different behaviors such as anxiety and food intake as well as cognition. Lastly, gaps in knowledge will be mentioned to stimulate further research.

Nesfatin-130-59 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-130-59-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-130-59 (0.1, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. Nesfatin-130-59 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-130-59 also reduced cookie intake during the novelty-induced hypophagia test (-62%, p < 0.05). Moreover, nesfatin-130-59 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-130-59 (p > 0.05). These results indicate an implication of nesfatin-130-59 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.

Current Understanding of the Role of Nesfatin-1.

Nesfatin-1 was discovered in 2006 and implicated in the regulation of food intake. Subsequently, its widespread central and peripheral distribution gave rise to additional effects. Indeed, a multitude of actions were described, including modulation of gastrointestinal functions, glucose and lipid metabolism, thermogenesis, mediation of anxiety and depression, as well as cardiovascular and reproductive functions. Recent years have witnessed a great increase in our knowledge of these effects and their underlying mechanisms, which will be discussed in the present review. Lastly, gaps in knowledge will be highlighted to foster further studies.