Brain histaminergic system: An emerging target for the treatment of feeding and eating-related disorders.

The aim of this study is to evaluate the expression of the histamine receptors, particularly focusing on the H4R in human renal tubules. The ex vivo evaluation was carried on specimens from human renal cortex. Primary and immortalized tubular epithelial cells (TECs) and the HK-2 cell line were used as in vitro models. Cells were pretreated for 10 min with chlorpheniramine maleate 10 μM (H1R antagonist), ranitidine 10 µM (H2R antagonist), GSK189254 1 µM (H3R antagonist) or JNJ7777120 10 µM (H4R antagonist), and then exposed to histamine (3 pM-10 nM) for 30 min. The ex vivo evaluation on specimens from human renal cortex was performed by immunohistochemistry. The expression of histamine receptors on primary and immortalized TECs and the HK-2 cell line was evaluated at both gene (RT-PCR) and protein (immunocytofluorescence) levels. The pharmacological analysis was performed by TR-FRET measurements of second messenger (IP3 and cAMP) production induced by histamine with or without the selective antagonists. Our data revealed the presence of all histamine receptors in human tubules; however, only TECs expressed all the receptors. Indeed, histamine elicited a sigmoid dose-response curve for IP3 production, shifted to the right by chlorpheniramine maleate, and elicited a double bell-shaped curve for cAMP production, partially suppressed by the selective H2R, H3R and H4R antagonists when each added alone, and completely ablated when combined together. Herein, we report the identification of all four histamine receptors in human renal tubules.

Surged Leptin/Ghrelin Secretion Associated With Anorexia Nervosa

Over the years, the standard of care for re-alimentation of patients admitted for the treatment of anorexia nervosa (AN) has been a conservative or cautious approach described as "start low and go slow." These traditional refeeding protocols advocate for a low-calorie diet that restricts carbohydrates, with the primary goal of hypothetically lowering the risk of refeeding syndrome (RFS) and its complication. However, no consensus exists for the optimal inpatient approach to refeeding children and adolescents with AN. There is still some disagreement about what constitutes an ideal pace for nutritional rehabilitation. Varying treatment protocols have emerged across the globe, often reflecting the preferences and biases of individual practitioners and contributing to the lack of a universally accepted protocol for refeeding in AN. Although it is widely accepted that low-caloric refeeding (LCR) is safe for inpatient treatment of AN, this strategy has been shown to have several significant drawbacks, leading to increased criticism of the LCR method. Research from the last decade has led to calls for a more aggressive refeeding protocol, one that suggests a higher caloric intake from the offset. As a result, this research aimed to conduct a systematic review of the existing literature on strategies for refeeding hospitalized pediatric/adolescent patients with AN and related eating disorders. We aimed to compare high-caloric refeeding (HCR) and LCR in terms of weight gain, length of stay, and risk of RFS. We conducted a thorough search of medical databases for abstracts published in English, including Google Scholar, PubMed, and MEDLINE, to find relevant studies published between 2010 and February 2023. Our focus was on articles that evaluated high versus low refeeding protocols in children and adolescents hospitalized for treating AN and related eating disorders. Only articles that reported on at least one of the outcome variables of interest, such as hypophosphatemia, weight gain, RFS, or length of hospital stay, were considered. This review included 20 full-text articles published in the last decade on the HCR protocol in children and adolescents, with a total sample size of 2191 participants. In only one of the 20 studies did researchers find evidence of a true clinical case of RFS. We, therefore, found no evidence that HCR increased the risk of RFS in adolescents, even in those with a very low body mass index (BMI). However, evidence suggests a lower BMI at the time of hospital admission is a better predictor of hypophosphatemia than total caloric intake.In conclusion, based on the evidence from this review, a high-caloric diet or rapid refeeding in children/adolescents suffering from AN may be both safe and effective, with serial laboratory investigations and phosphate supplementation as needed. Hence, more research, particularly, randomized controlled trials, is required to help shape an evidence-based refeeding guidelineoutlining target calorie intakes and rates of advancement to assist clinicians in the treatment of adolescents with AN and related eating disorders.

Regulation of food intake and energy expenditure is crucial to maintain a stable body weight. Excessive energy intake combined with inadequate energy expenditure leads to obesity, which is co-morbid with many devastating diseases such as cancer, cardiovascular diseases, and infertility. The hypothalamus plays a pivotal role in the regulation of energy balance. It integrates signals from both the external environment and internal milieu to modulate feeding and energy expenditure to maintain energy homeostasis. Neuropeptides are critical molecular mediators underlying many important energy homeostatic functions of the hypothalamus. Thus, a detailed knowledge of the role of hypothalamic peptides and their receptors in controlling feeding, metabolism, and energy expenditure is essential to understand the causes of obesity and related metabolic disorders. Urocortin 3 (Ucn 3) is a member of the corticotropin-releasing factor (CRF) family of peptides. The CRF family plays a critical role in coordinating aspects of the stress response including stimulation of the hypothalamic-pituitary-adrenal axis, behavioral arousal, and energy adaptation through suppression of feeding and promotion of energy mobilization. Centrally-injected Ucn 3 suppresses feeding, elevates blood glucose concentration and body temperature, and stimulates the hypothalamic-pituitary-adrenal axis, indicating that central Ucn 3 may be involved in regulating energy homeostasis and the stress response. Cell bodies of neurons expressing Ucn 3 are located in the hypothalamus and medial amygdala. Direct injection of Ucn 3 into the ventromedial hypothalamus (VMH) has been shown to potently suppress feeding and rapidly elevate blood glucose levels. Anatomical studies revealed that Ucn 3 neurons in the anterior parvicellular part of the paraventricular nucleus of the hypothalamus (PVHap) provide the major Ucn 3 afferent input into the VMH, therefore it is conceivable that the Ucn 3 PVHap-VMH pathway may play a critical role in modulating energy homeostasis in response to stress. Currently, little is known about the Ucn 3 neurons in the PVHap. In my thesis studies, I combined functional and anatomical approaches to characterize these neurons in great detail. I first showed that acute stress rapidly stimulates Ucn 3 expression in the PVHap. A functional neuroanatomical tracing study identified a number of brain areas that provide stress-activated input into the PVHap area. In the forebrain, the bed nucleus of the stria terminalis, lateral septal nucleus, the medial amygdala, and a number of nuclei in the hypothalamus including the VMH, the arcuate nucleus, the posterior nucleus, and the ventral premammillary nucleus provide stress-activated input into the PVHap. In the brainstem, stress-sensitive input originates from the periaqueductal gray, the nucleus of the solitary tract, and the ventrolateral medulla. These areas are potentially important in mediating the stress-induced activation of Ucn 3 neurons in the PVHap. I then determined that Ucn 3 neurons in the PVHap…

Obesity and associated metabolic syndrome are growing global problems which have taken an epidemic stature over recent decades. According to International Obesity Task Force and World Health Organization’s guidelines, approximately 1.0 billion adults are currently overweight with Body Mass Index (BMI) of 25 – 29.9 kg/m2, and 475 million are obese (BMI greater than or equal to 30 kg/m2). Prevalence of threats from these disorders poses a major risk for many deleterious, chronic diseases, such as type-2 diabetes (T2D), stroke and coronary heart disease and cancers, thus exerting a heavy toll on healthcare economy and demanding a big attention from clinicians, researchers and policy makers. Through recent research, considerable advances have been made towards therapeutic approaches for obesity and related metabolic disorders, for example, a few newer drugs with better pharmacological activities, and gastric surgery for treating severe obesity. However, obesity tide continues to escalate in particular in developed countries. Thus, the challenge to preventive and therapeutic success remains, partly due to the fact that obesity pathophysiology is orchestrated by complex interactions among environment, genetic predisposition and behaviors. With this pressing experimental and clinical need, extensive research in this direction is ongoing, be it in the field of gaining mechanistic insights into neuroendocrine regulation of body weight, or targeting inhibition of peripheral and central anabolic factors or stimulation of catabolic signals. Earlier research has linked obesity to a chronic imbalance between energy intake and expenditure, that results in inordinate lipid depositions in adipose tissues which activate various stress responsive and inflammatory pathways. Recent research developments have linked defects of hypothalamic signaling to obesity and metabolic syndrome which is considerably expanding the scope of the mechanistic understanding. This special edition in Reviews in Endocrine and Metabolic Disorders highlights a series of recent advancements in understanding the brain regulation of metabolic disorders and potential new therapeutic options. Blevins and Ho provide an excellent overview about the implications of oxytocin signaling disruption in obesity manifestation and the potential of peripheral or central oxytocin treatment as a weight loss therapeutic target. Considering oxytocin treatment has shown promising results in a recent clinical trial, further research in experimental and clinical levels is much needed for developing a safe and effective treatment option. M. H. Tschop and his colleagues focus on an important but often neglected subject of sexual dimorphism and role of gonadal hormones in obesity and metabolic diseases. They deliberated on astrocytic estrogen-mediated neuroendocrine regulation of body weight and metabolic homeostasis. He and Feng discussed the role of crosstalk between estrogen and leptin signaling in metabolic balance, a very relevant and timely topic of active research in the light of weight management and breast cancer development. Seli and Horvath delve upon this important topic describing how vaginal birth in advantage to experimental C-section induces higher hippocampal Ucp2 mRNA expression thus enabling metabolic adaptation to available nutrients and regulation of postnatal neuronal differentiation, axonal outgrowth, synapse formation and adult behaviors. The importance of adult neuronal modifications has been further highlighted by Purkayastha and Cai while discussing an obesogenic effect of prolong high-fat diet-induced hypothalamic inflammation via disruption of hypothalamic neurogenesis and neural stem cells. Butterick et al discussed if hypothalamic neuropeptide orexin A may promote obesity resistance by increasing spontaneous physical activity. T. K. Lam and his colleagues discussed on how two pancreatic hormones, insulin and glucagon, could work in consonance in the brain for the regulation of energy and glucose homeostasis. M. S. Lee and group discussed the prospect of hypothalamic autophagy on becoming a novel therapeutic target for appetite control and whole-body metabolism. L. Rui has given a comprehensive overview of the homeostatic and hedonic circuits of the hypothalamus and the hind brain that regulate food intake and energy expenditure, as well as potential neural defects that contribute to obesity pathogenesis. These in-depth reviews provide a wealth of information and can expand readers’ understandings of the cellular and mechanistic bases of obesity and related disorders while illuminating the current therapeutic options and potential drug targets. Additionally, many of these reviews provide angles to promote research interest to address the lingering obstacles of effective and safe therapeutic options for long-term weight loss and reducing metabolic disorders. It is our hope that continuing research will lead up to novel therapeutic strategies for this complex cluster of difficult-to-treat metabolic disorders and diseases. As Guest Editor of this issue, I would take this opportunity to thank the contributing authors who have enlightened us on some very important and timely topics and newer approaches. My sincere gratitude is to the editorial and production staff of Springer for patiently accommodating all our contributions.

Leptin and the regulation of food intake, energy homeostasis and immunity with special focus on periparturient ruminants

Combined treatment with H1 and H4 receptor antagonists reduces inflammation in a mouse model of atopic dermatitis

H4R antagonists are anti‐inflammatory in murine models of asthma. Here, we examined the specific ability of H4R to modulate TH2 cell function and the associated downstream effects of Th2 cytokine modulation such as: inflammation, mucus cell hyperplasia, MMP expression and collagen disposition, using a selective H4R antagonist. Mice were sensitized i.p. to ovalbumin in alum followed by repeated challenge with ovalbumin. Lungs were lavaged and tissues collected. Therapeutic treatment resulted in decreased lung TH2 cytokines, IL13 and IL5, and decreased cell influx into the lung. In addition to the reduction of eosinophils, there was a reduction in CD3+ cells. Cultured T cell re‐stimulated with antigen ex‐vivo had reduced production of TH2 cytokines. IL13 dependent markers of lung remodeling such as goblet cell hyperplasia, MMP‐9 expression, and total lung collagen were reduced. Thus, we demonstrate that the anti‐inflammatory properties of H4R antagonists include modulation of TH2 cell function, resulting in a reduction of TH2 derived IL13. Consequently, H4R antagonists reduce cardinal signs of asthma such as inflammation and lung remodeling, suggesting their potential as a novel human therapeutics.

Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity.

Fasting activates neuropeptide Y neurons in the arcuate nucleus and the paraventricular nucleus in the rhesus macaque

Objective To explore the abnormalities of amplitude of low-frequency fluctuation (ALFF) in the resting-state functional magnetic resonance imaging (rs-fMRI) of first-episode medication-naive schizophrenia before and after antipsychotic drugs therapy, the correlation between brain activity and clinical syndromes was to be analyzed. Methods This prospective study was approved by the local ethical committee, and written informed consent was obtained from all participants. 21 antipsychotic-naive first-episode patients with schizophrenia and 25 healthy individuals were recruited and underwent resting-state functional MR imaging. The patients were re-scanned at the end of 3 months after the antipsychotic treatment. The differences of ALFF between patients and controls were analyzed with two-sample t test, the differences of ALFF in patients before and after antipsychotic drugs therapy were analyzed with two-sample t test. Results (1) The scores of Global Assessment of Functioning Scale, PANSS total score, PANSS positive score, PANSS negative score and PANSS general psychopathology score were significantly improved after antipsychotic drugs therapy (t=6.45, 5.13, 3.98, 3.29, 4.32; P 10), resting-state ALFF in schizophrenia patients significantly increased in anterior cingulate cortex (ACC) and right lentiform nucleus (uncorrected, t=3.60, 3.44; P 10). (3) After antipsychotic drugs therapy for 3 months, the ALFF values increased in bilateral cuneus and decreased in left ACC compared with baseline(uncorrected, t=3.91, -4.42; P 10). (4) The ALFF values in the anterior cingulate cortex(ACC) at baseline were positively correlated with negative symptoms scores of PANSS (r=0.594, P=0.005). The ALFF values in the left MOG at baseline were negatively correlated with total scores of PANSS (r=-0.464, P=0.034). Conclusions This study provides evidence for resting state brain activity abnormalities of some brain regions in patients with schizophrenia. ACC and occipital gyrus are the key brain regions and may be responsible for certain schizophrenic symptoms, which could contribute to explore the neuropharmacology mechanisms of schizophrenia. Key words: Schizophrenia; Magnetic resonance imaging; Resting-state; Amplitude of low frequency fluctuation

Although obesity is an epidemic threat to general health worldwide, an effective treatment has yet to be found. Insights into weight-regulatory pathways will accelerate the identification of new molecular targets for anti-obesity agents. 5'-AMP-activated protein kinase (AMPK) is an enzyme activated during low cellular energy charge. In peripheral tissues, the activation of AMPK influences various metabolic pathways, including glucose uptake, glycolysis, and fatty acid oxidation, all of which help to re-establish a normal cellular energy balance. AMPK is also present in the neurons of the hypothalamus, a critical center in the regulation of energy homeostasis. Recent studies from our group and others have shown that many factors (alpha-lipoic acid, leptin, insulin, ghrelin, glucose, 2-deoxyglucose, etc.) cause an alteration in hypothalamic AMPK activity that mediates effects on feeding behavior. Hypothalamic AMPK also appears to play a role in the central regulation of energy expenditure and peripheral glucose metabolism. These data indicate that hypothalamic AMPK is an important signaling molecule that integrates nutritional and hormonal signals and modulates feeding behavior and energy metabolism.

New therapeutic approaches to target gut-brain axis dysfunction during anorexia nervosa

Pharmacological approaches to feeding behaviour and eating disorders

Numerous peripheral signals contribute to the regulation of food intake and energy homeostasis. Mechano- and chemoreceptors signaling the presence and energy density of food in the gastrointestinal (GI) tract contribute to satiety in the immediate postprandial period. Changes in circulating glucose concentrations appear to elicit meal initiation and termination by regulating activity of specific hypothalamic neurons that respond to glucose. Other nutrients (e.g., amino acids and fatty acids) and GI peptide hormones, most notably cholecystokinin, are also involved in short-term regulation of food intake. However, the energy density of food and short-term hormonal signals by themselves are insufficient to produce sustained changes in energy balance and body adiposity. Rather, these signals interact with long-term regulators (i.e., insulin, leptin, and possibly the orexigenic gastric peptide, ghrelin) to maintain energy homeostasis. Insulin and leptin are transported into the brain where they modulate expression of hypothalamic neuropeptides known to regulate feeding behavior and body weight. Circulating insulin and leptin concentrations are proportional to body fat content; however, their secretion and circulating levels are also influenced by recent energy intake and dietary macronutrient content. Insulin and leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, ensuring that feeding is triggered before body energy stores become depleted. Dietary fat and fructose do not stimulate insulin secretion and leptin production. Therefore, attenuated production of insulin and leptin could lead to increased energy intake and contribute to weight gain and obesity during long-term consumption of diets high in fat and/or fructose. Transcription of the leptin gene and leptin secretion are regulated by insulin-mediated increases of glucose utilization and appear to require aerobic metabolism of glucose beyond pyruvate. Other adipocyte-derived hormones and proteins that regulate adipocyte metabolism, including acylation stimulating protein, adiponectin, diacylglycerol acyltransferase, and perilipin, are likely to have significant roles in energy homeostasis.