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G protein–coupled receptor (GPCR) signaling is a dynamic process involving various conformational intermediates in addition to those captured in static three-dimensional structures. Here, we used newly developed G protein peptidomimetics to characterize the interactions of the ghrelin receptor (GHSR) with G proteins. Coupling to the G protein peptidomimetic not only affected the conformational features of the cytoplasmic regions of the receptor where the G protein binds but also allosterically affected the extracellular ligand-binding pocket. These conformational and allosteric changes increased the affinity of G protein–coupled GHSR for the endogenous agonist ghrelin. In addition, our data identified different complexes along the G protein activation pathway that differed in the engagement of the Gαq C-terminal helix. Given that this helix is the main link between the activated receptor and the Gα nucleotide-binding pocket, these findings suggested a stepwise process involving distinct states in GPCR-catalyzed G protein activation. Collectively, our results provide evidence for the dynamic behavior of GPCR–G protein signaling complexes, with such dynamics most likely contributing to signaling selectivity and/or efficacy. Editor's summary: Ghrelin is a peptide hormone that acts on its G protein–coupled receptor (GPCR) to stimulate appetite and food intake. Signal transduction by GPCRs requires activation of intracellular G proteins in a process involving transient conformational changes in both the receptor and the Gα subunit. Mannes et al. developed synthetic peptides that mimicked the stabilizing effect of Gαq-containing heterotrimers on the active conformation of the ghrelin receptor. Biochemical assays using these peptidomimetics demonstrated that G protein coupling allosterically increased the receptor's affinity for ghrelin and that G protein activation occurred through a series of distinct interactions with the receptor. The findings demonstrate that G protein activation is a multistep process that may also affect the sensitivity of the ghrelin receptor. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

Liver-expressed antimicrobial peptide 2 (LEAP2) has recently emerged as a novel hormone that reduces food intake and glycemia by acting through the growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor. This discovery has led to a fundamental reconceptualization of GHSR's functional dynamics, now understood to be under a dual and opposing regulation. LEAP2 exhibits several distinctive features. LEAP2 is released by hepatocytes and enterocytes, 2 cell types that lack classical regulatory secretory mechanisms and may respond differently to nutrient signals. LEAP2 is also found in higher concentrations in plasma than ghrelin, even under energy deficit conditions, and modulates GHSR by inhibiting both ghrelin-dependent and ghrelin-independent activities. Given these characteristics, LEAP2 appears to play a major role in regulating GHSR activity in vivo, extending beyond simple ghrelin antagonism and being crucial for the long-term regulation of energy balance. A deeper understanding of how LEAP2 functions may clarify the functional implications of GHSR in different physiological contexts and unlock new therapeutic strategies for treating obesity, diabetes, and other metabolic disorders. [ABSTRACT FROM AUTHOR]

Liver-expressed antimicrobial peptide 2 (LEAP-2) was originally discovered as an antimicrobial peptide that plays a vital role in the host innate immune system of various vertebrates. Recent research discovered LEAP-2 as an endogenous antagonist and inverse agonist of the GHSR1a receptor. By acting as a competitive antagonist to ghrelin, LEAP-2 influences energy balance and metabolic processes via the ghrelin–GHSR1a signaling pathway. LEAP-2 alone or the LEAP-2/ghrelin molar ratio showed potential as therapeutic targets for obesity, diabetes, and metabolic disorders. This review explores the recent advances of LEAP-2 in immune modulation and energy regulation, highlighting its potential in treating the above diseases. [ABSTRACT FROM AUTHOR]

Ghrelin is a gut hormone that enhances food intake and growth hormone secretion through its G-protein coupled receptor, the growth hormone secretagogue receptor (GHSR). Recently, we have shown that ghrelin interacts with syndecans (SDCs), a family of membrane proteins known to modulate hypothalamic appetite signaling. Here, we investigated whether SDCs impact ghrelin signaling at GHSR by assessing ghrelin-induced intracellular Ca2+ mobilization (iCa2+) and inositol phosphate 1 (IP1) production in HEK293 cells. Compared with controls, the overexpression of SDCs dose-dependently increased the maximum iCa2+ response two-to four-fold, without affecting EC50. The IP1 response was similarly amplified by SDCs, but it also indicated that they reduce constitutive (ghrelin-independent) activity of GHSR. These enhanced responses occurred despite a SDC dose-dependent reduction in plasma membrane GHSR levels. Although ghrelin-stimulated Gαq activation was unaltered by SDC1 expression, it failed to restore iCa2+ responsiveness in GNAQ/11 knockout cells, indicating dependence on Gαq/11, not another Gα subunit. This suggests that SDCs modulate either signaling downstream of Gαq/11 or quenching of β-arrestin2 recruitment to GHSR. Indeed, expression of SDCs at levels that only modestly suppress cell surface receptor reduced ghrelin-induced β-arrestin2 recruitment by ~80%. SDC co-expression also delayed the peak β-arrestin2 response. However, peak β-arrestin2 recruitment follows the peak iCa2+ response, making it unclear whether reduced β-arrestin2 recruitment potentiated Ca2+ signaling. Altogether, SDCs enhanced iCa2+/IP1 and reduced β-arrestin2 recruitment by GHSR in response to ghrelin, likely by modulating signaling downstream of Gαq. This could be a novel mechanism through which SDCs affect metabolism and obesity. [ABSTRACT FROM AUTHOR]

It is widely recognized that developing bi- or multifunctional opioid compounds could offer a valuable approach to pain management with fewer side effects compared to single-target compounds. In this study, we designed and characterized two novel chimeric peptides, EM-1-DLS and EM-2-DLS, incorporating endomorphins (EMs) and the ghrelin receptor antagonist [D-Lys3]-GHRP-6 (DLS). Functional assays demonstrated that EM-1-DLS and EM-2-DLS acted as κ-opioid receptor (κ-OR)-preferring agonists, weak μ-opioid receptors (μ-OR) and ghrelin receptor (GHSR) agonists. Upon intracerebroventricular (i.c.v.) administration in mice, both EM-1-DLS and EM-2-DLS exhibited dose- and time-dependent antinociceptive effects in the tail withdrawal test. EM-1-DLS demonstrated the highest antinociceptive potency among the peptides, with an ED 50 approximately 8-fold greater than EM-1, while EM-2-DLS showed comparable effects to EM-2. The antinociceptive actions of EM-1-DLS involved activation of GHS-R1α, μ-OR, and κ-OR, whereas EM-2-DLS acted via GHS-R1α, δ-OR, and κ-OR pathways. Additionally, acute antinociceptive tolerance was investigated, revealing that EM-1-DLS induced a tolerance ratio of 2.33-fold, significantly lower than the 5.19-fold ratio induced by EM-1. Cross-tolerance ratios between the chimeric peptides and EMs ranged from 0.92 to 1.76, indicating reduced tolerance compared to EMs alone. These findings highlight the potential of these chimeric peptides to mitigate pain with diminished tolerance development, suggesting a promising strategy for the development of new analgesic therapies with improved safety profiles. • Novel chimeric peptides of EMs and [D-Lys3]-GHRP-6 were synthesized. • The chimeric peptides were agonists of κ-OR, μ-OR and GHSR. • The peptides induced good antinociception in acute pain in mice. • EM-1-DLS reduced the acute tolerance relative to that of EM-1. • The cross-tolerance between the chimeric peptides and EMs was low. [ABSTRACT FROM AUTHOR]

Simple Summary: Semi-natural pastures provide the primary food source for sheep, whose grazing activity contributes to preserving grassland biodiversity. However, summer drought stress reduces the nutritional value of pastures, with negative consequences on the morpho-functional characteristics of the digestive system and other sheep systems. Understanding the molecules linked to energy metabolism is important for identifying suitable markers of tissue functionality and ensuring animal well-being, a key factor in sustainable livestock production. Ghrelin plays a role in food intake and is involved in tissue regeneration, repair and diseases at the skin level, even if information about this organ is very scarce. This study aims to analyze the ghrelin system in the skin of sheep grazing on seminatural pasture during the spring–summer season and compare differently fed animals. The results indicate that ghrelin and its receptor are localized in sheep skin appendices, with greater expression in animals fed with diet supplementation. This finding suggests that diet may influence the proliferative activity of the hair follicle through variations in the ghrelin system expression. These insights could be a useful tool for the breeders to counteract the negative effects of increasing summer aridity. Ghrelin (GhRL) is an orexigenic hormone influenced by nutritional state. It plays a role in skin repair and diseases, though little information exists regarding its function in this organ. GhRL and its receptor were investigated in the skin of sheep under different feeding conditions to explore GhRL system presence and possible modifications due to diet. Three-year-old female sheep were free to graze from June to the pasture maximum flowering (MxF group) and from this period to maximum dryness addicted (Exp group) or not (MxD group) with 600 gr/die/head of barley and corn. Skin samples were processed for immunohistochemistry and real-time PCR. The immunostaining showed the presence of the GhRL system in skin appendages. Indeed, the ligand was localized in the hair follicles whereas the receptor was also observed in sweat glands and smooth muscle cells. The expression of both genes was significantly higher in the Exp group (3.6 and 2.9 folds respectively, p < 0.05) compared with the MxF group. These results suggest that the GhRL system is involved in the regulation of hair follicles and sweat glands. In addition, diet supplementation may positively modulate the expression of GhRL and its receptor in the skin. [ABSTRACT FROM AUTHOR]

Background/Objectives: Ghrelin and growth hormone-releasing peptide 6 (GHRP-6) are peptides which can stimulate GH release, acting through the same receptor. Ghrelin and its receptor have been involved in reward sensation and addiction induced by natural and artificial drugs, including nicotine. The present study aimed to investigate the impacts of ghrelin and GHRP-6 on the horizontal and vertical activity in rats exposed to chronic nicotine treatment followed by acute nicotine withdrawal. Methods: Male and female Wistar rats were exposed daily to intraperitoneal (ip) injection with 2 mg/kg nicotine or saline solution for 7 days, twice a day (at 8:00 and at 20:00). In parallel, the rats were exposed daily to an intracerebroventricular (icv) injection with 1 μg/2 μL ghrelin or 1 μg/2 μL GHRP-6 or saline solution for 7 days, once a day (at 8:00). On the morning of the eighth day (12 h after the last ip administration) and the ninth day (24 h after the last ip administration), the horizontal and vertical activity were monitored in a conducta system. Results: On the eighth day, in nicotine-treated rats a significant hyperactivity was observed, that was reduced significantly by ghrelin and GHRP-6. On the ninth day, in nicotine-treated rats a significant hypoactivity was assessed that was reversed significantly by ghrelin and GHRP-6. Conclusions: Based on the present results, the changes in horizontal and vertical activity observed after 12 and 24 h of nicotine withdrawal can be attenuated by ghrelin and GHRP-6. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Cachexia is a complex and multifactorial syndrome, which is a current, worldwide treatment challenge, and concerns most of the patients with cancer. The issue is characterized by anorexia, skeletal muscle loss, adipose tissue wasting, involuntary weight loss, malnutrition, and poor appetite due to dysfunction of metabolism and chronic, systemic inflammation. Additionally, it impacts oncological treatment and a decline in Quality of Life. The review aims to explore the latest research, innovations, and potentials in the treatment of cachexia. Material and methods: The review was based on research of articles published from 2019 to 2024 on the PubMed database using the following keywords: cancer cachexia, palliative care, and cachexia pharmacotherapy. Results: Anamorelin, a selective ghrelin receptor agonist showed effectiveness in weight gain and appetite improvement. Also, myostatin inhibitors protect muscles and promote their growth due to suppression of myostatin. Ponsegromab, a GDF-15 inhibitor, significantly and directly enhanced muscle mass, appetite, and quality of life, with good safety. Modern antiinflammatory medications like momelotynib or tocilizumab, reduced the concentration of proinflammatory cytokines and improved quality of life, however, but posed immunosuppression risk. Pentoxifylline declined inflammation and chemotherapy toxicity, and improved body weight and survival. Cannabinoids alleviated chemotherapy-induced nausea but were ineffective for weight and quality of life. Conclusions: Therapeutic approaches target various aspects of cachexia due to its complex pathophysiology. Anamorelin, ponsegromab, and myostatin inhibitors have clinical potential. Modern antiinflammatory drugs and pentoxifylline offer supportive benefits. Further research is vital for developing effective and safe treatment guidelines for cancer cachexia. [ABSTRACT FROM AUTHOR]

Obesity has been identified as a rapidly rising pandemic within the developed world, potentially increasing the risks of type 2 diabetes and cardiovascular disease. Various studies have identified a positive association between stress, elevated cortisol levels and obesity. Mechanisms of the stress response lead to hyperpalatable food preference and increased appetite through the activation of the HPA axis, elevated cortisol and the resulting interactions with the dopaminergic system, neuropeptide Y, ghrelin, leptin and insulin. The methodology of this review involved a Systematic Search of the Literature with a Critical Appraisal of papers considering ashwagandha, mediation and mindfulness in relation to mechanisms of the stress response. It incorporated 12 searches yielding 330 hits. A total of 51 studies met the inclusion criteria and were critically appraised with ARRIVE, SIGN50 and Strobe checklists. Data from the 51 studies was extracted, coded into key themes and summarized in a narrative analysis. Thematic analysis identified 4 key themes related to ashwagandha and 2 key themes related to meditation. Results provide an overview of evidence assessing the efficacy of ashwagandha and meditation in relation to weight loss interventions by supporting the stress response and the pathways highlighted. Results of Clinical studies indicate that ashwagandha supports weight loss through reduced stress, cortisol and food cravings. Pre-clinical studies also suggest that ashwagandha possesses the capacity to regulate food intake by improving leptin and insulin sensitivity and reducing addictive behaviors through dopamine regulation. Clinical studies on meditation indicate it may enhance a weight loss protocol by reducing the stress response, cortisol release and blood glucose and improving eating behaviors. Key teaching points: Chronic exposure to stress may promote obesogenic eating behaviors through the activation of the HPA axis and the resulting interactions between cortisol and the dopaminergic system, neuropeptide Y, ghrelin, leptin and insulin. Ashwagandha may support weight loss via appetite regulation through stress reduction, enhance leptin sensitivity, glucose tolerance, insulin sensitivity and dopamine regulation. Withaferin A, ashwagandha's primary withanolide, may be the active compound responsible for its capacity to regulate leptin and insulin. Meditation may support weight loss through stress and cortisol reduction, improve glucose tolerance and insulin sensitivity and regulate eating behavior. [ABSTRACT FROM AUTHOR]

Context The liver/foregut satiety hormone liver-expressed antimicrobial peptide 2 (LEAP2) is an inverse agonist at the acyl ghrelin receptor (GHSR), increasing after food intake and decreasing after bariatric surgery and short-term nonsurgical weight loss, but effects of long-term dietary weight loss are unknown. Objective The objective of this study was to examine and compare the effects of these interventions on fasting and postprandial plasma LEAP2 and investigate potential metabolic mediators of changes in plasma LEAP2. Methods Plasma LEAP2 was measured in a previously published 2-year trial comparing standard medical management (SMM) (including 600-kcal/day deficit) with duodenal-jejunal bypass liner (DJBL, Endobarrier) insertion (explanted after 1 year) in adults with obesity and inadequately controlled type 2 diabetes mellitus. Results In the SMM group (n = 25-37), weight decreased by 4.3%, 8.1%, 7.8%, and 6.4% at 2, 26, 50, and 104 weeks and fasting plasma LEAP2 decreased from baseline mean ± SD 15.3 ± 0.9 ng/mL by 1.7, 3.8, 2.1, and 2.0 ng/mL, respectively. Absolute/decreases in fasting plasma LEAP2 positively correlated with absolute/decreases in body mass index, glycated hemoglobin A1c, fasting plasma glucose, serum insulin, homeostatic model assessment for insulin resistance, and serum triglycerides. Despite greater weight loss in the DJBL group (n = 23-30) at 26 to 50 weeks (10.4%-11.4%), the decrease in fasting plasma LEAP2 was delayed and attenuated (vs SMM), which may contribute to greater weight loss by attenuating GHSR signaling. Plasma LEAP2 did not increase with weight regain from 50 to 104 weeks after DJBL explant, suggesting a new set point with weight loss maintenance. Increases in plasma LEAP2 after a 600-kcal meal (10.8%-16.1% at 1-2 hours) were unaffected by weight loss, improved glucose metabolism, or DJBL insertion (n = 9-25), suggesting liver rather than duodenum/jejunum may be the primary source of postprandial LEAP2 secretion. Conclusion These findings add to our understanding of the regulation and potential physiological role of plasma LEAP2. [ABSTRACT FROM AUTHOR]

Various roles of intestinal flora in the gut-brain axis response pathway have received enormous attention because of their unique position in intestinal flora-derived metabolites regulating hormones, inducing appetite, and modulating energy metabolism. Reward pathways in the brain play a crucial role in gut-brain communications, but the mechanisms have not been methodically understood. This review outlined the mechanisms by which leptin, ghrelin, and insulin are influenced by intestinal flora-derived metabolites to regulate appetite and body weight, focused on the significance of the paraventricular nucleus and ventromedial prefrontal cortex in food reward. The vagus nerve and mitochondria are essential pathways of the intestinal flora involved in the modulation of neurotransmitters, neural signaling, and neurotransmission in gut-brain communications. The dynamic response to nutrient intake and changes in the characteristics of feeding activity requires the participation of the vagus nerve to transmit messages to be completed. SCFAs, Bas, BCAAs, and induced hormones mediate the sensory information and reward signaling of the host in the complex regulatory mechanism of food selection, and the composition of the intestinal flora significantly impacts this process. Food reward in the process of obesity based on gut-brain communications expands new ideas for the prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

Copyright of Baghdad Science Journal is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Alzheimer's disease imposes an increasing burden on aging Western societies. The disorder most frequently appears in its sporadic form, which can be caused by environmental and polygenic factors or monogenic conditions of incomplete penetrance. According to the authors, in the majority of cases, Alzheimer's disease represents an aggravated form of the natural aging of the central nervous system. It can be characterized by the decreased elimination of amyloid β1–42 and the concomitant accumulation of degradation-resistant amyloid plaques. In the present paper, the dysfunction of neuropeptide regulators, which contributes to the pathophysiologic acceleration of senile dementia, is reviewed. However, in the present review, exclusively those neuropeptides or neuropeptide families are scrutinized, and the authors' investigations into their physiologic and pathophysiologic activities have made significant contributions to the literature. Therefore, the pathophysiologic role of orexins, neuromedins, RFamides, corticotrope-releasing hormone family, growth hormone-releasing hormone, gonadotropin-releasing hormone, ghrelin, apelin, and natriuretic peptides are discussed in detail. Finally, the therapeutic potential of neuropeptide antagonists and agonists in the inhibition of disease progression is discussed here. [ABSTRACT FROM AUTHOR]

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut‐released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long‐term effects of UnAG in age‐associated muscle atrophy and contractile dysfunction in mice. Four‐month‐old and 18‐month‐old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%–30% with age, which was partially protected against by UnAG. Specific force, force per cross‐sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA‐seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Contemporary Pediatrics is the property of Xiangya Medical Periodical Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Social isolation affects physical functioning owing to psychological stress. We constructed a rat model to clarify the unexplored effects of social isolation and to determine whether environmental changes as an intervention against social isolation can reduce the stress-inducing effects of social isolation on physiological factors. Eight-week-old male rats were divided into three groups: group-housed, isolated, and intervention. Group-housed rats were kept 2 animals per cage. Isolated rats were kept 1 rat per cage. The intervention group alternated between the isolation and group-housed conditions. All rats were euthanized after 21 days. Their plasma, masseter muscles, and lower limb muscles were collected. Body weight, food intake, locomotor activity, muscle weight, and plasma corticosterone, ghrelin, and myostatin levels were measured. The results indicated that there were no significant differences between the group-housed and intervention groups for all outcomes. However, weight gain, food intake, and plasma corticosterone levels were higher in the isolated group than in the group-housed group. Plasma myostatin levels were higher in the isolated group than in the intervention group. Plasma ghrelin concentrations were lower in the isolated group than in the group-housed or intervention groups. In the isolated group, locomotor activity decreased compared to that in the intervention group. The lower limb muscle weight ratio also decreased in the isolated group compared to that in the group-housed and intervention groups. In conclusion, isolation decreased physical activity and affected body weight, food intake, and muscle weight; these changes were associated with corticosterone as a stress marker, ghrelin as an appetite-related factor, and myostatin, which is a growth inhibitor of skeletal muscles. Moreover, these changes were suppressed when the isolation time was reduced in the intervention group. The present study suggests that intermittent breaking of isolation may reduce the physical effects of isolation. [ABSTRACT FROM AUTHOR]

Ghrelin is a hormone consisting of 28 amino acids. Growth hormone secretagogue receptor (GHSR) is a receptor for ghrelin, which is expressed in the brain, pituitary gland, and adrenal glands, especially in the hypothalamus. The binding of ghrelin to the receptor 1a subtype mediates most of the biological effects of ghrelin. Ghrelin has a close relationship with the onset of psychosis. Ghrelin can affect the onset of psychosis by regulating neurotransmitters such as dopamine, γ‐aminobutyric acid (GABA), and 5‐hydroxytryptamine (5‐HT) through the hypothalamus–pituitary–adrenal (HPA) axis, brain–gut axis, the mesolimbic dopamine system, and other ways. Ghrelin activates neuropeptide Y (NPY) in the hypothalamic arcuate nucleus (ARC) through the GHSR. Ghrelin binds to neurons in the ventral tegmental area (VTA), where it promotes the activity of dopamine neurons in the nucleus accumbens (NAcs) in a GHSR–dependent way, increasing dopamine levels and the reward system. This article summarized the recent research progress of ghrelin in depression, anxiety, schizophrenia, anorexia nervosa (AN), and bulimia nervosa (BN), and emphasized its potential application for psychiatric disorders treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion The knowledge and proficiency of primary care practitioners (PCPs) in diagnosing and managing irritable bowel syndrome (IBS) remain generally low and variable internationally. This variability is partly due to a lack of familiarity with the Rome Foundation diagnostic criteria and treatment guidelines for this condition.We conducted an electronic survey of PCPs in the United States and nine European countries to assess their understanding of IBS pathophysiology; the use of Rome IV criteria in diagnosis, knowledge of and frequency in prescribing various recommended treatments; and the likelihood of referring patients with suspected IBS to subspecialists.Most PCPs in the United States and Europe perceive IBS as a diagnosis of exclusion rather than a definitive diagnosis. They also believe IBS is underdiagnosed in primary care and challenging to diagnose confidently. The majority of PCPs consider diet as a crucial component of IBS management. Notably, US PCPs reported greater confidence than their European counterparts in recommending dietary interventions such as increased dietary fiber, a low FODMAP diet, and gluten restriction. Conversely, both groups exhibited moderate to high confidence in recommending over‐the‐counter treatments. European PCPs showed greater confidence in treating IBS with antispasmodics and secretagogues, while US PCPs expressed greater confidence in prescribing neuromodulators. Additionally, US PCPs were more likely to refer patients with suspected IBS to a gastroenterologist, whereas both US and European PCPs showed similar referral patterns to dietitians and referred very few patients to mental health providers. Both US and European PCPs reported that IBS is moderately to extremely difficult to treat effectively and emphasized the importance of a strong and longitudinal doctor‐patient relationship in managing the condition.Despite the Rome Foundation recommendations and criteria to support a positive diagnosis of IBS, most PCPs still rely on exclusionary investigations such as endoscopy and a serologic workup, while a significant percentage suggest referring patients to gastroenterologists. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a highly prevalent and debilitating disorder of gut–brain interaction (DGBI) affecting millions globally. It imposes a significant burden on healthcare systems and is a leading cause of workplace absenteeism. IBS is classified into several subtypes based on predominant presenting symptoms, including IBS with constipation (IBS-C) and IBS with diarrhea (IBS-D), with each requiring targeted approaches to treatment. Some treatments, such as psychotherapy, dietary intervention, and medications like tricyclic antidepressants, are nonspecific and recommended for managing IBS symptoms across all subtypes. In contrast, therapies like secretagogues for IBS-C and eluxadoline or rifaximin for IBS-D are subtype-specific. However, many IBS treatments carry conditional recommendations and are based on low-certainty evidence, emphasizing the need for further research to expand the available treatment options. This review compares the latest IBS management guidelines from the American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), British Society of Gastroenterology (BSG), and European Society for Neurogastroenterology and Motility (ESNM). Pharmacologic and non-pharmacologic therapies, including established and emerging interventions, will be explored to provide a comprehensive guide to management. [ABSTRACT FROM AUTHOR]

ABSTRACT Copper (Cu) is an effective additive in feed for promoting growth. Growth dan axis comprising growth hormone (GH), somatostatin (SS) and GH‐releasing hormone (GHRH), with ghrelin regulating their release. The growth‐promoting effects of Cu are closely related to ghrelin, but the specific mechanism behind the relationship remains unknown. We investigated the adjustment of ghrelin synthesis and secretion by Cu. Sprague–Dawley rats were fed basal diets with an addition of 0, 120 or 240 mg/kg Cu sulfate for 28 day to establish a growth‐promoting model. Signalling molecules relevant to ghrelin synthesis and secretion were detected and mechanistically explored using enzyme‐linked immunosorbent assay, quantitative reverse‐transcription polymerase chain reaction and Western blot analysis. The 120 mg/kg supplement improved growth performance; significantly increased the serum levels of ghrelin, ghrelin O‐acyltransferase (GOAT), acylated ghrelin (AG), GH, and reactive oxygen species (ROS) and decreased those of SS; significantly increased the mRNA and protein expression of ghrelin, GOAT, ghrelin receptor (GHS‐R1α), and activator protein 1 (AP‐1); increased the phosphorylation ratio of JNK and p38 MAPK; and inhibited the mRNA and protein expression of SS and SS receptor subtype 2 (SSTR2) in gastric fundic gland tissues. Thus, Cu may affect gastric ghrelin synthesis at the transcriptional level by activating the JNK/p38 MAPK pathway through increased ROS levels and regulating the activation of the downstream redox‐sensitive transcription factor AP‐1. SS plays a crucial determinant role in ghrelin regulation via intragastric Cu. Cu promotes GOAT activity and ghrelin secretion by inhibiting SS secretion, affecting AG levels, and promoting ghrelin acylation through ghrelin/GOAT/GHS‐R1α system, modulating ghrelin secretion. [ABSTRACT FROM AUTHOR]

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism. [ABSTRACT FROM AUTHOR]

Background: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW. Methods: We examined the effects of RKT on food intake and neuronal c‐Fos expression in restraint stress‐ and cholecystokinin octapeptide‐induced anorexia in male rats. Key Results: RKT treatment significantly restored stress‐ and cholecystokinin octapeptide‐induced decreased food intake. RKT increased c‐Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase‐immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D‐Lys3]‐GHRP‐6. RKT increased the number of c‐Fos/orexin‐double‐positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT‐induced increase in food intake and c‐Fos expression in the LH, VTA, and NAc. RKT increased c‐Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D‐Lys3]‐GHRP‐6. Conclusions & Inferences: RKT may restore appetite in subjects with anorexia through ghrelin‐ and orexin‐dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW. [ABSTRACT FROM AUTHOR]

Introduction: Because MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there is currently a tremendous interest in whetherMRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. Therefore, we sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2. Methods: Various relevant in vitro, ex vivo, and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FceR1-mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic relationships because both antagonists studied were shown to be human specific. Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, Compound B, being orally active and demonstrating high potency in blocking Substance P-mediated degranulation using freshly isolated human skin mast cells with half maximal inhibitory concentration (IC50) at 0.42 nM. Compound B also potently blocked Substance P-stimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils. Conclusion: These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell-driven allergic skin disorders such as chronic spontaneous urticaria. [ABSTRACT FROM AUTHOR]

Introduction: Daily torpor is an active hypothermic phenomenon that is observed in some mammals and birds during fasting. A decrease in blood pressure has also been observed in torpor; however, there remains a lack of knowledge of the underlying mechanism. We have previously reported that ghrelin, an orexigenic hormone, has a hypothermic effect and is essential for the induction and maintenance of torpor. It is also known that the ghrelin secretion is enhanced during fasting and that ghrelin receptors are distributed in the cardiovascular system. Therefore, this study was conducted to test the hypothesis that ghrelin is actively involved in the regulation of blood pressure during torpor induction. Methods: Male wild-type and ghrelin gene-deficient mice were generated by homologous recombination as previously reported. Mice, 10 weeks old, were included in this study and housed five per cage. The mice were maintained on a 12-h light/dark cycle (lights on from 7:00 to 19:00) with access to food and water ad libitum. Results: The continuous measurement of blood pressure using a telemetry system showed that induction of torpor by fasting did not decrease blood pressure in ghrelin gene-deficient mice. The analysis of heart rate variability revealed that sympathetic nerve activity was predominant in ghrelin-deficient mice during fasting. Furthermore, these features were cancelled by administration of a ghrelin receptor agonist and were comparable to those in wild-type mice. Discussion: In this study, we showed that blood pressure was elevated in ghrl-/- mice and that the blood pressure rhythm was abnormal. Furthermore, we showed that the ghrelin gene deficiency does not cause sufficient blood pressure reduction upon entry into the torpor, and that the administration of the ghrelin receptor agonist, GHRP-6, causes blood pressure reduction associated with torpor. Thus, we have shown for the first time that the active role of ghrelin is essential for active blood pressure reduction associated with torpor, and that this action is mediated by the inhibition of sympathetic nerve activity by ghrelin. [ABSTRACT FROM AUTHOR]

Background: Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. Methods: Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. Results: Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-β1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-β1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. Conclusion: Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis. Author summary: There is evidence that Echinococcus granulosus (E.g) is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of hepatic cystic Echinococcosis (CE). Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in the regulation of CE progression is not clear. The present study demonstrated that Ghrelin is highly expressed in the early stage of hepatic E.g infection and may act mainly on hepatic stellate cells and T cells, exerting biological effects to inhibit Th1-type cellular immunity, the Myd88/NF-κB and TGF-β1/Smad3 pathways and agonize Th2-type cellular immunity, which in turn suppresses host expression of immunoinflammation and fibrosis. However, this biological effect of Ghrelin may regulate the progression of CE. [D-Lys3]-GHRP-6, as a Ghrelin receptor blocker, is expected to be a drug target against CE. In addition, we found protoscoleces of E.g with gene expression of Ghrelin, which also provides some evidence that Ghrelin regulates the disease progression of CE. Our study reveals the possible regulatory role and mechanism of Ghrelin in the process of hepatic E.g infection. In-depth studies could help to further unravel the disease mechanisms of CE and provide potential targets for therapy. [ABSTRACT FROM AUTHOR]

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of Piezo1 (Ghrl-Piezo1−/−) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1−/− mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1−/− mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver. Editor's summary: The appetite-stimulating hormone ghrelin promotes hepatic lipid accumulation. Zhang et al. investigated the regulation of hepatic lipid homeostasis by Piezo1, a mechanosensitive ion channel that is activated when food ingestion stretches the stomach and that suppresses ghrelin production. Mice lacking Piezo1 in ghrelin-producing cells in the stomach developed hepatic steatosis, which was reversed by pharmacologically blocking the ghrelin receptor. Gastric bead implantation, which mimicked the mechanical stretch induced by food intake, reduced hepatic steatosis in control mice on a normal diet or with diet-induced obesity but not in the conditional knockout mice. Thus, Piezo1 in ghrelin-producing cells could be targeted to treat metabolic dysfunction–associated steatotic liver disease, the most prevalent liver disorder worldwide. —Wei Wong [ABSTRACT FROM AUTHOR]

Growth hormone secretagogue receptor 1a (GHS-R1a), also known as the ghrelin receptor, is an important nutrient sensor and metabolic regulator in both humans and rodents. Increased GHS-R1a expression is observed in the hippocampus of both Alzheimer's disease (AD) patients and AD model mice. However, the causal relationship between GHS-R1a elevation in the hippocampus and AD memory deficits remains uncertain. Here, we find that increasing GHS-R1a expression in dCA1 pyramidal neurons impairs hippocampus-dependent memory formation, which is abolished by local administration of the endogenous antagonist LEAP2. GHS-R1a elevation in dCA1 pyramidal neurons suppresses excitability and blocks memory allocation in these neurons. Chemogenetic activation of those high GHS-R1a neurons during training rescues GHS-R1a overexpression-induced memory impairment. Moreover, we demonstrate that increasing GHS-R1a expression in dCA1 pyramidal neurons hampers these neurons' ability to encode spatial memory and reduces engram size in the dCA1 region. Finally, we show that GHS-R1a deletion mitigates spatial memory deficits in APP/PS1 mice with increased GHS-R1a expression in the hippocampus. Our findings reveal a negative, causal relationship between hippocampal GHS-R1a expression and memory encoding, and suggest that blocking the abnormal increase in GHS-R1a activity/expression may be a promising approach to improve memory and treat cognitive decline in AD. Mechanistic modeling reveals that increased GHS-R1a expression in hippocampal neurons impairs memory formation, suggesting that targeting GHS-R1a activity could improve memory and mitigate cognitive decline in AD. [ABSTRACT FROM AUTHOR]

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF- 03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation. [ABSTRACT FROM AUTHOR]

The fused in sarcoma (FUS) protein is a DNA/RNA binding protein from the teneleven translocation protein family that is associated with neurodegeneration, and it has been shown to promote cell proliferation through the growth hormone/insulin-like growth factor 1 (Gh/Igf-1) signaling pathway. The zig-zag eel (Mastacembelus armatus) is a newly discovered species exhibiting sexual dimorphism in growth, and the potential role of fus in the growth and development of this species remains largely unknown. Herein, we analyzed the homology, conserved domains, evolutionary characteristics, and conserved syntenies of fus in several teleost species. The expression of fus was predominant in the brain and exhibited sexual dimorphism in the brain, muscle, and liver of zig-zag eels. We found thatmicroRNA (miR)-146-5p, miR-489-3p, and 24 other miRNAs were targeted to the fus 3' untranslated region, which might affectmuscle and bone development in adults. The igf1, insulin-like growth factor 1 receptor a (igf1ra), insulin-like growth factor 2 receptor (igf2r), growth hormonereleasing hormone-like receptor (ghrhrl), growth hormone secretagogue receptor type 1 (ghsr), and glucocorticoid receptor (gr) genes contained a higher abundance of GU-rich fus motifs compared to the other four genes analyzed in zig-zag eels. We also measured the expression of fus mRNA during fish culture at various stocking densities to further elucidate the relationship between fus expression and the Gh/Igf-1 axis. After 100 days of fish cultivation, the expression of fus and ghrhrl decreased and the expression of ghrh and gr increased as the culture density increased (p < 0.05). The expression of fus exhibited a remarkable positive correlation with a specific growth rate. These results indicate that fus mediates growth differences by regulating the expression of several growth-related genes including Gh/Igf-1 axis genes in zig-zag eels. [ABSTRACT FROM AUTHOR]

Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1–14]. For this, two experimental models were used: (i) LEAP2[1–14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1–14]or MK677. Perinatal GHSR modulation by LEAP2[1–14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood. [ABSTRACT FROM AUTHOR]

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected. [ABSTRACT FROM AUTHOR]

Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown. We investigated the effects of ghrelin infusion on appetite and glucose tolerance in individuals with obesity before and 3 mo after SG. Twelve participants scheduled for SG were included. Before and 3 mo after surgery, a mixed-meal test followed by an ad libitum meal test was performed with concomitant infusions of acyl-ghrelin (1 pmol/kg/min) or placebo. Infusions began 60 min before meal intake to reach a steady state before the mixed-meal and were continued throughout the study day. Two additional experimental days with 0.25 pmol/kg/min and 10 pmol/kg/min of acyl-ghrelin infusions were conducted 3 mo after surgery. Both before and after SG, postprandial glucose concentrations increased dose dependently during ghrelin infusions compared with placebo. Ghrelin infusions inhibited basal and postprandial insulin secretion rates, resulting in lowered measures of β-cell function, but no effect on insulin sensitivity was seen. Ad libitum meal intake was unaffected by the administration of ghrelin. In conclusion, ghrelin infusion increases postprandial plasma glucose concentrations and impairs β-cell function before and after SG but has no effect on ad libitum meal intake. We speculate that the lower concentration of ghrelin after SG may impact glucose metabolism following this procedure. NEW & NOTEWORTHY: Ghrelin's effect on glucose tolerance and food intake following sleeve gastrectomy (SG) was evaluated. Acyl-ghrelin was infused during a mixed-meal and ad libitum meals before and 3 mo after surgery. Postprandial glucose concentrations increased during ghrelin infusions, both before and after surgery, while insulin production was inhibited. However, ad libitum meal intake did not differ during ghrelin administration compared with placebo. The decreased ghrelin concentration following SG may contribute to the glycemic control after surgery. [ABSTRACT FROM AUTHOR]

The aim of this study was to observe the effect and mechanism of single point and compatibility acupoints on diabetic gastroparesis rats. The effect difference between single point and compatible points of diabetic gastroparesis rat's model rats was evaluated by hematoxylin and eosin, immunohistochemistry and Western blot. The expression of Cajal, neuronal nitric oxide synthase, nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 proteins in gastric tissue and the expression of hypothalamic mesencephalic intestinal peptides neuronal nitric oxide synthase, ghrelin and somatostatin proteins were observed. Compared with the model group, the mediastinal and circumferential muscle cells of the gastric smooth muscle of CV12 and ST36 were relatively compact. The grooves of stomach were slightly changed, and the main cells, adenium cells and cervical mucous cells were arranged more neatly than those in model group. Macrophages decreased in gastric submucosa and mucosal muscle layer. The arrangement of muscle cells in the mediastinal muscle layer and the circumferential muscle layer of CV12+ST36 gastric smooth muscle was relatively dense, which was more obvious than that in single point CV12 and ST36. After acupuncture treatment, the expression of neuronal nitric oxide synthase in gastric and hypothalamic were all increased compared with model group. In the expression of interstitial cells of Cajal, CV12+ST36 was better than CV12 than ST36. And compared with model group, the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 was increased, and CV12+ST36 group was higher than that of single point CV12 and ST36 (p<0.01). In terms of central regulation, the expression of somatostatin protein in hypothalamus was observed in the single point group CV12 (2955.43±206.24, p<0.01), the combined point group CV12+ST36 (2066.88±116.81, p<0.01) was increased compared with model group. The expression of ghrelin in hypothalamus decreased in CV12 (76.00±6.16, p<0.01), but increased in ST36 (288.00±31.12, p<0.01). And CV12+ST36 (234.00±19.95, p<0.05) was increased after acupuncture treatment. The compatibility of acupoints is an important part of acupuncture treatment. Acupuncture improved gastric smooth muscle, the number and structure of interstitial cells of Cajal, and mucosal protection, and the compatibility acupoints was better than the single point, which may be increased the nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 expression to protect diabetic gastroparesis rat's from oxidative stress. [ABSTRACT FROM AUTHOR]

The article discusses various scientific research topics, including topological optics, plant science, evolution, spectroscopy, neuroscience, metabolism, GPCR signaling, immunotherapy, regeneration, infertility, aging of the brain and heart, parenting, 2D materials, inorganic chemistry, and biomaterials. Each study provides valuable insights into different aspects of science, from understanding the projection of higher-dimensional crystals to exploring the genetic basis of root hydropatterning in maize. The research findings contribute to a deeper understanding of complex scientific phenomena and offer potential directions for future studies and applications. [Extracted from the article]

Background: Anamorelin is a selective ghrelin receptor agonist approved for cancer cachexia in Japan. Little is known about predictors of anamorelin efficacy. This study aimed to assess the effect of diabetes on the efficacy and safety of anamorelin in patients with cancer cachexia. Methods: Medical records of patients with advanced non-small-cell lung, gastric, pancreatic, or colorectal cancer who received anamorelin between January 2021 and March 2023 were retrospectively reviewed. The diabetic (DM) group included patients with a confirmed diagnosis of type 2 diabetes mellitus, random plasma glucose of ≥ 200 mg/dL, or hemoglobin A1c of ≥ 6.5%. The maximum body weight gain and adverse events during anamorelin administration were compared between the DM and non-DM groups. Patients with a maximum body weight gain ≥ 0 kg were classified as the responders. Results: Of 103 eligible patients, 31 (30.1%) were assigned to the DM group. The DM group gained less weight (median of −0.53% vs. + 3.00%, p < 0.01) and had fewer responders (45.2% vs. 81.9%, p < 0.01) than the non-DM group. The odds ratio for non-response in the DM group was 6.55 (95% confidential interval 2.37–18.06, p < 0.01), adjusted by age and performance status. The DM group had a higher cumulative incidence of hyperglycaemic adverse events (72.2% vs. 6.3%, p < 0.01) and more discontinuations due to hyperglycaemic adverse events (25.8% vs. 4.2%, p < 0.01) than the non-DM group. Conclusions: Patients with diabetes and cancer cachexia are less likely to gain weight with anamorelin despite a high risk of hyperglycaemic adverse events. [ABSTRACT FROM AUTHOR]

The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa‐miR‐204‐5p, hsa‐miR‐211‐5p, hsa‐miR‐30, hsa‐miR‐3163, hsa‐miR‐33a‐3p, hsa‐miR‐548, hsa‐miR‐561‐3p, hsa‐miR‐7856‐5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases. [ABSTRACT FROM AUTHOR]

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti‐obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide‐based and small molecule‐based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti‐obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O‐acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite‐reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half‐life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti‐obesity therapies. [ABSTRACT FROM AUTHOR]

This article provides a list of references to scientific articles on various topics related to personalized and precision medicine. The references cover subjects such as cardiovascular risk assessment, biomarkers for cancer, machine learning in healthcare, circadian rhythms, and personalized medicine. These articles can serve as a valuable resource for library patrons conducting research on these specific topics. [Extracted from the article]

Context Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. Objective Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). Methods Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. Results Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. Conclusion Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C. [ABSTRACT FROM AUTHOR]

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center. Hibernating ground squirrels have negligible hunger despite a months-long period of food deprivation and cold exposure. Here, authors show that prolonged anorexia is enabled by inhibition of the hypothalamic feeding center due to central hypothyroidism. [ABSTRACT FROM AUTHOR]

Background: Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated. Methods: In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests. Results: We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects. Conclusions: This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH‐SY5Y cells against 1‐methyl‐4‐phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC‐1α pathway. In this study, an animal model was established using a neurotoxin, 1‐methyl‐4phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP‐induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP‐treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis‐related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP‐treated mice by increasing PINK1/Parkin‐mediated mitophagy and AMPK/SIRT1/PGC‐1α‐mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD. Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH‐SY5Y cells against 1‐methyl‐4‐phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC‐1α pathway. In this study, an animal model was established using a neurotoxin, 1‐methyl‐4phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP‐induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP‐treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis‐related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP‐treated mice by increasing PINK1/Parkin‐mediated mitophagy and AMPK/SIRT1/PGC‐1α‐mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD. [ABSTRACT FROM AUTHOR]

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)–producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2 -expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)–expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2 -expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation–induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice. [ABSTRACT FROM AUTHOR]

Background: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. Case presentation: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child–Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. Conclusions: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring. [ABSTRACT FROM AUTHOR]

The potential role of the ghrelin receptor, also known as the growth hormone secretagogue receptor (GHSR), within the nucleus accumbens (NAcc) in regulating drug addiction and feeding has been documented; however, the pattern of its expression in this site remains elusive. In this study, we characterized the expression patterns of GHSR1a and 1b, two subtypes of GHSRs, within the NAcc of the rat brain by immunohistochemistry. We visually detected GHSR signals, for the first time, at the protein level in the NAcc in which they were mostly expressed in neurons including both medium spiny neurons (MSNs) and non-MSNs. Furthermore, GHSR1a was found expressed as localized near the cellular membrane or some in the cytoplasm, whereas GHSR1b expressed solely throughout the large cytoplasmic area. The existence and subcellular expression pattern of GHSRs in the NAcc identified in this study will contribute to improving our understanding about the role of GHSR-mediated neurosignaling in feeding and drug addiction. [ABSTRACT FROM AUTHOR]

Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both adlibitum feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control. [ABSTRACT FROM AUTHOR]

Triacylglycerols (TAGs) are a major fat component in human milk. Since gastric lipase produces 1,2-diacylglycerol from TAGs, we focused on the bioactivity of human milk-derived diacylglycerols in stomach cells. Ghrelin is produced in the stomach and acts as an important regulator of growth hormone secretion and energy homeostasis. In this study, we showed that 1-oleoyl-2-palmitoylglycerol (OP) increased ghrelin secretion, whereas 1,3-dioleoyl-2-palmitoylglycerol (OPO), a major component of human milk TAGs, did not increase ghrelin secretion in the ghrelin-secreting cell line, MGN3-1. Therefore, diacylglycerol OP may directly contribute to the regulation of ghrelin secretion. We also found that 2-palmitoylglycerol and 1- and 2-oleoylglycerol increased ghrelin secretion. Finally, we demonstrated that intracellular cAMP levels and preproghrelin and ghrelin O-acyl transferase expression levels were enhanced by OP treatment in MGN3-1 cells. This may represent an example of a novel mother-infant interaction mediated by fat components derived from human breast milk. [ABSTRACT FROM AUTHOR]

Reducing ghrelin by ghrelin gene knockout (GKO), ghrelin-cell ablation, or high-fat diet feeding increases islet size and β-cell mass in male mice. Here we determined if reducing ghrelin also enlarges islets in females and if pregnancy-associated changes in islet size are related to reduced ghrelin. Islet size and β-cell mass were larger (P =.057 for β-cell mass) in female GKO mice. Pregnancy was associated with reduced ghrelin and increased liver-expressed antimicrobial peptide-2 (LEAP2; a ghrelin receptor antagonist) in wild-type mice. Ghrelin deletion and pregnancy each increased islet size (by ∼19.9-30.2% and ∼34.9-46.4%, respectively), percentage of large islets (>25 µm2×103, by ∼21.8-42% and ∼21.2-41.2%, respectively), and β-cell mass (by ∼15.7-23.8% and ∼65.2-76.8%, respectively). Neither islet cross-sectional area, β-cell cross-sectional area, nor β-cell mass correlated with plasma ghrelin, although all positively correlated with LEAP2 (P =.081 for islet cross-sectional area). In ad lib-fed mice, there was an effect of pregnancy, but not ghrelin deletion, to change (raise) plasma insulin without impacting blood glucose. Similarly, there was an effect of pregnancy, but not ghrelin deletion, to change (lower) blood glucose area under the curve during a glucose tolerance test. Thus, genetic deletion of ghrelin increases islet size and β-cell cross-sectional area in female mice, similar to males. Yet, despite pregnancy-associated reductions in ghrelin, other factors appear to govern islet enlargement and changes to insulin sensitivity and glucose tolerance in the setting of pregnancy. In the case of islet size and β-cell mass, one of those factors may be the pregnancy-associated increase in LEAP2. [ABSTRACT FROM AUTHOR]

The article discusses advancements in the design and application of hydrogels, particularly in biomedical fields, focusing on the integration of semiconducting functionalities through solvent exchange methods. Topics discussed include the impact of agrochemicals on insect populations, the rapid spread of wildfires in the U.S., and innovative approaches to protein design using machine learning techniques.

The article discusses the physiological process of torpor and hibernation in endothermic animals, including mice. Torpor is a hypoactive metabolic state that animals enter during periods of low temperatures and food scarcity to conserve energy. The central nervous system, particularly the hypothalamus, plays a crucial role in regulating torpor. The article presents recent findings on the neural circuits involved in torpor regulation, specifically focusing on the antero-preoptic area, medial preoptic area, and dorsomedial hypothalamus. The article also highlights the need for further research to understand the mechanisms underlying torpor and hibernation in different animal species, including humans. [Extracted from the article]