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• Human GH transgenic rats exhibit hyperphagia and obesity from a young age. • TG rats showed hypercorticosteronemia accompanying enlarged adrenal glands. • ADX blunted, and glucocorticoids supplement alleviated hyperphagia only in TG rats. • Group housing prevented hyperphagia and hypercorticosteronemia in TG rats. Hyperphagia and subsequent obesity are important public health issues due to the associated risks of developing serious diseases. Certain stressors play a major role in the development of hyperphagia. In previous studies, we established a line of human growth hormone transgenic (TG) rats that exhibit hyperphagia and obesity from a young age. We recently demonstrated that voluntary running on a running wheel alleviates hyperphagia in TG rats. Wheel running provides environmental enrichment for rodents and plays a role in relieving stress. These results suggested that stress is the major factor inducing hyperphagia in TG rats. Thus, in the present study, we evaluated activation of the hypothalamus–pituitary–adrenal axis. TG rats showed bilateral enlargement of adrenal glands and hypercorticosteronemia, although their hypothalamic CRH level was comparable to that of wild-type (WT) rats. The ACTH-immunoreactive area was larger and the serum ACTH level in the dark phase was higher in TG rats than in WT rats. Adrenalectomy reduced the food intake of TG rats to a level comparable to that in WT rats, and supplying glucocorticoids recurred hyperphagia in TG rats. These treatments did not affect the food intake of WT rats. Rearing TG rats under group housing prevented hyperphagia and hypercorticosteronemia. These results suggest that glucocorticoids are appetite stimulants, and that TG rats exhibit increased sensitivity to the appetite-stimulating effect of glucocorticoids. [ABSTRACT FROM AUTHOR]

The article in MedComm discusses how the phosphorylation of mitochondrial fission factor (MFF) in the liver, triggered by pro‐opiomelanocortin (POMC) activation, regulates mitochondrial fragmentation and glucose production. This study sheds light on the role of liver mitochondria as a nutrient sensor and its impact on metabolic adaptation to anticipatory nutritional states. The findings suggest potential targets for intervention in metabolic diseases like diabetes and obesity by understanding the AKT/MFF pathway and its influence on hepatic glucose production. The research highlights the importance of food perception in orchestrating metabolic homeostasis and offers insights into developing therapeutic strategies for metabolic disorders. [Extracted from the article]

Objective: To synthesise young person and family member perspectives on processes of change in family therapy for anorexia nervosa (AN), including systemic family therapy and manualised family-based treatments, to obtain an understanding of what helps and hinders positive change. Method: A systematic search of the literature was conducted to identify qualitative studies focussing on experiences of therapeutic change within family therapies for AN from the perspectives of young people and their families. Fifteen studies met inclusion criteria and underwent quality appraisal following which they were synthesised using a meta-synthesis approach. Results: Six overarching themes were generated: "A holistic focus on the young person's overall development"; "The therapeutic relationship as a vehicle for change"; "The therapist's confinement to a script and its impact on emotional attunement"; "A disempowering therapeutic context"; "Externalisation of the eating disorder (ED)"; and "The importance of family involvement". Positive change was helped by understanding and support given to the young person's overall development including their psychological, emotional, social and physical wellbeing, positive therapeutic relationships, relational containment within the family system and externalising conversations in which young people felt seen and heard. Positive change was hindered by inflexibility in the treatment approach, counter-effects of externalisation, negative experiences of the therapist, a narrow focus on food-intake and weight, as well as the neglect of family difficulties, emotional experiences, and psychological factors. Conclusions: Positive change regarding the young person's eating-related difficulties ensued in the context of positive relational changes between the young person, their family members, the therapist and treatment team, highlighting the significance of secure and trusting relationships. The findings of this review can be utilised by ED services to consider how they may adapt to the needs of young people and their families in order to improve treatment satisfaction, treatment outcomes, and in turn reduce risk for chronicity in AN. Plain English summary: This review synthesises the views of young people and their family members regarding their perspectives of therapeutic change within family therapies for Anorexia Nervosa (AN), including both manualised eating disorder-focussed family therapy models (family-based treatment; FBT and AN-focussed family therapy; FT-AN), as well as systemic family therapy (SyFT), to understand which aspects of these treatment approaches are helpful versus hindering to recovery from an eating disorder (ED). Parental involvement was crucial in facilitating the restoration of physical health through the process of parents taking temporary responsibility for the young person's eating behaviours until they can feed themselves again. However, treatment often failed to acknowledge and address the psychological and emotional difficulties that made the young person vulnerable to developing AN, as well as the psychological distress caused by increasing food-intake and weight. A positive therapeutic relationship in which families felt well supported by their therapist was important in providing containment during a time of familial strain and instability, yet there was a need for greater flexibility and individualisation within manualised ED-focussed family therapy approaches, particularly FBT. The findings highlight the importance of eliciting the young person's voice to enhance their personal agency in treatment and the value of therapeutic space to improve family functioning and enhance family unity. Lastly, they illuminate the need for manualised ED-focussed family therapy models to allow space for the therapist to emotionally attune to young people and families in order to contain their experience of distress. [ABSTRACT FROM AUTHOR]

Simple Summary: Stress during hospitalization can significantly impact cats, prompting the exploration of various strategies, including non-pharmacological approaches, to alleviate stress. However, certain situations may necessitate the use of anxiolytic medications like gabapentin and alprazolam to reduce stress levels. This study aimed to assess the effectiveness of gabapentin or alprazolam in cats undergoing short-term hospitalization on stress reduction, food consumption, and pain scores. Sixty cats undergoing elective ovariohysterectomy were divided into three groups, gabapentin-, alprazolam- or placebo-treated, and received treatment twice daily for two days. The study found that both gabapentin and alprazolam significantly reduced stress levels. Cats treated with alprazolam exhibited increased food intake, while those receiving gabapentin showed lower pain scores on the first postoperative day. However, both treatments led to increased levels of sedation. The study suggests that incorporating anxiolytics may be an effective adjunctive strategy for improving the experience of short-term hospitalization in cats. This prospective, randomized study aimed to assess the anxiolytic efficacy of gabapentin or alprazolam in cats during short-term postoperative hospitalization. Sixty cats were randomly assigned to three groups (gabapentin-treated [100 mg per cat], alprazolam-treated [0.125 mg per cat], or placebo-treated), with treatments administered twice daily for two days. Stress levels were evaluated using Cat Stress Scores, serum cortisol, and glucose concentrations. Pain scores, food consumption, and adverse effects such as sedation were also monitored. Fifty-five cats completed the study. Both medications demonstrated similar reductions in stress levels. Cats receiving gabapentin had lower pain scores, while those receiving alprazolam exhibited significantly increased food intake on the first postoperative day. However, both medications resulted in comparable levels of sedation. In the context of postoperative hospitalization, pharmacological intervention with anxiolytics could be effective in reducing stress levels. Despite potential side effects, gabapentin and alprazolam may contribute to an improved quality of short-term hospitalization for cats. [ABSTRACT FROM AUTHOR]

Chronic pruritus (CP) is defined as an unpleasant sensation causing a desire to scratch and lasting > 6 weeks. It has a multifactorial etiology but is more frequently associated with chronic inflammatory dermatoses and systemic disorders. Psychogenic pruritus and neurological disorders are other less common etiologies, while, in some patients, it is idiopathic. CP appears to be processed by non-histaminergic pathway, contributing to its complexity and therapeutic challenge. Moreover, regardless of the etiology, it is multidimensional, including cognitive, motivational and affective components. There is a close link between psychological distress and pruritus, with particular clinical expression in chronic inflammatory dermatoses, involving the activation of the hypothalamic-pituitary-adrenal axis (and its cutaneous equivalent), the sympathetic nervous system, the release of hormones and peptides, the role of immune cells (T and B cells, macrophages) and immune-related cells in the skin (mast cells, dendritic cells and keratinocytes). Moreover, there is strong evidence that psychological factors influence the experience of pruritus. CP can also cause psychiatric disorders, including but not limited to anxiety and depression, and also lead to significant quality of life (QoL) impairment. Thereby, although a psychodermatological assessment should ideally be carried out in the context of a specific psychodermatology consultation, a brief mental health assessment could be part of the general dermatological approach to these patients. Considering that mental health, QoL and pruritus are closely linked, psychotherapeutic interventions and/or psychotropic drugs should thus be considered in some patients as an adjunct to the pharmacological treatment of CP. [ABSTRACT FROM AUTHOR]

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior. The neurobiological mechanisms underlying the fast acting and long-lasting effects of these drugs are not fully understood. Here authors show that the psychedelic psilocin increases reactivity in the paraventricular nucleus of the hypothalamus (PVN) in male rats but does not change acute stress response. Male reactivity changes are driven by active threat responding, with clinical implications. [ABSTRACT FROM AUTHOR]

The human ileum contains a high density of enteroendocrine L-cells, which release the appetite-suppressing hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in response to food intake. Recent evidence highlighted the potential role of food structures in PYY release, but the link between food structures, ileal metabolites, and appetite hormone release remains unclear owing to limited access to intact human ileum. In a randomized crossover trial (ISRCTN11327221; isrctn.com), we investigated the role of human ileum in GLP-1 and PYY release by giving healthy volunteers diets differing in fiber and food structure: high-fiber (intact or disrupted food structures) or low-fiber disrupted food structures. We used nasoenteric tubes to sample chyme from the intact distal ileum lumina of humans in the fasted state and every 60 min for 480 min postprandially. We demonstrate the highly dynamic, wide-ranging molecular environment of the ileum over time, with a substantial decrease in ileum bacterial numbers and bacterial metabolites after food intake. We also show that high-fiber diets, independent of food structure, increased PYY release compared with a low-fiber diet during 0 to 240 min postprandially. High-fiber diets also increased ileal stachyose, and a disrupted high-fiber diet increased certain ileal amino acids. Treatment of human ileal organoids with ileal fluids or an amino acid and stachyose mixture stimulated PYY expression in a similar profile to blood PYY concentrations, confirming the role of ileal metabolites in PYY release. Our study demonstrates the diet-induced changes over time in the metabolite environment of intact human ileum, which play a role in PYY release. Editor's summary: The digestion of different foods as they travel the length of the gastrointestinal tract is highly orchestrated, and the true complexity of this process is just beginning to be understood. Dagbasi et al. studied how fiber content and food structure affect nutrient metabolism and release of appetite-controlling peptides such as PYY in the human ileum. They found that high dietary fiber consumption, regardless of the extent of food processing, promoted ileal PYY (but not GLP-1) release in healthy volunteers. This PYY release was promoted by ileal metabolites, showing how what we eat may signal to the intestine to feed back on whole-body physiology. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Background: Jianqu has been used to alleviate symptoms in patients with functional dyspepsia, but its specific anti-functional dyspepsia effect is still unclear. Therefore, our study aimed to investigate the impact of Jianqu on functional dyspepsia in mice. Methods: The phytochemical profile of Jianqu was analyzed by UPLC-Q-TOF-MS. Subsequently, Kunming mice were fed a high-calorie or high-protein diet (HCHP) for 7 days, and then orally treated with vehicle or Jianqu (1.62 g/kg body weight (b. w.) and 3.25 g/kg b. w.) for 10 days. A carbon powder solution was used to detect the gastric emptying and intestinal transit rate. The pathological changes in stomach and duodenum were evaluated by hematoxylin-eosin staining. The occludin, claudin-1, ZO-1 and CD45 expression was measured by immunocytochemical staining. Importantly, the serum gastrointestinal hormones were detected by ELISA. In addition, the gut microbiota composition was determined using 16S rRNA gene sequencing. The cecal short chain fatty acids were assessed by gas chromatography. Results: In general, 17 phytochemical compounds were identified from Jianqu, which significantly improved the gastric emptying rate and intestinal transit rate (p < 0.01), increased the body weight and food intake (p < 0.0001) in HCHP mice as well. Though HCHP did not cause significant pathological lesions in the gastrointestinal tract, increased the expression of CD45 in the duodenum (p < 0.05) was observed. Notably, Jianqu attenuated this abnormal expression of CD45 (p < 0.05). The levels of serum gastrointestinal hormones were significantly normalized by Jianqu intervention (p < 0.05). Moreover, Jianqu increased the relative abundance of Roseburia as well as short chain fatty acids levels in cecum (p < 0.05). Conclusion: The present results showed that Jianqu alleviated dyspeptic symptoms in HCHP mice possibly through reducing the duodenal leukocyte infiltration, and regulating the expression of gastrointestinal hormones. These effects may be partly related to the increasing cecal short chain fatty acids levels probably via gut microbial modulation. [ABSTRACT FROM AUTHOR]

Summary: A systematic search was conducted in Medline Ovid, Embase, Scopus, and Cochrane Central Register of Controlled Trials up until March 2021 following PRISMA guidelines. Studies included evaluated ghrelin, GLP‐1, PYY or appetite sensation via visual analogue scales (VASs) before and after Roux‐en‐Y gastric bypass (RYGB) in adults. A multilevel model with random effects for study and follow‐up time points nested in study was fit to the data. The model included kcal consumption as a covariate and time points as moderators. Among the 2559 articles identified, k = 47 were included, among which k = 19 evaluated ghrelin, k = 40 GLP‐1, k = 22 PYY, and k = 8 appetite sensation. Our results indicate that fasting ghrelin levels are decreased 2 weeks post‐RYGB (p = 0.005) but do not differ from baseline from 6 weeks to 1‐year post‐RYGB. Postprandial ghrelin and fasting GLP‐1 levels were not different from pre‐surgical values. Postprandial levels of GLP‐1 increased significantly from 1 week (p < 0.001) to 2 years post‐RYGB (p < 0.01) compared with pre‐RYGB. Fasting PYY increased at 6 months (p = 0.034) and 1 year (p = 0.029) post‐surgery; also, postprandial levels increased up to 1 year (p < 0.01). Insufficient data on appetite sensation were available to be meta‐analyzed. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism. [ABSTRACT FROM AUTHOR]

Introduction: Lipocalin 2 (Lcn2) is a key factor in appetite suppression. However, the effect of Lcn2 on appetite in terms of sex differences has not been thoroughly studied. Methods: Young (3-month-old) whole-body Lcn2 knockout (Lcn2−/−) mice were fed a normal diet (ND) or high-fat diet (HFD) for 8 weeks to investigate obesity, food intake, serum metabolism, hepatic lipid metabolism, and regulation of gastrointestinal hormones. Results: Lcn2 deficiency significantly increased the body weight and food intake of male mice when fed ND instead of HFD and females when fed HFD but not ND. Compared to wild-type (WT) male mice, the adiponectin level and phosphorylated form of adenosine 5′-monophosphate-activated protein kinase (AMPK) in the hypothalamus were both increased in ND-fed Lcn2−/− male mice but decreased in HFD-fed Lcn2−/− male mice. However, in female mice, adiponectin and its energy metabolism pathway were not altered. Instead, estradiol was found to be substantially higher in ND-fed Lcn2−/− female mice and substantially lower in HFD-fed Lcn2−/− female mice compared with WT female mice. Estradiol alteration also caused similar changes in ERα in the hypothalamus, leading to changes in the PI3K/AKT energy metabolism pathway. It suggested that the increased appetite caused by Lcn2 deficiency in male mice may be due to increased adiponectin expression and promotion of AMPK phosphorylation, while in female mice it may be related to the decrease of circulating estradiol and the inhibition of the hypothalamic ERα/PI3K/AKT energy metabolism pathway. Conclusion: Lcn2 plays in a highly sex-specific manner in the regulation of appetite in young mice. [ABSTRACT FROM AUTHOR]

Background: Cyproheptadine is an easily available over-the-counter first-generation antihistaminic that is often used as an appetite stimulant. Although it is usually a safe drug, rare instances of drug-induced liver injury may occur. Case presentation: We report a case of cholestatic liver injury secondary to cyproheptadine in a young pharmacy student with chronic hepatitis B and review the literature of cyproheptadine-induced liver injury. Conclusion: Although cyproheptadine is largely a safe drug, its potential for significant liver toxicity cannot be ignored. [ABSTRACT FROM AUTHOR]

The brain possesses intricate mechanisms for monitoring sodium (Na) levels in body fluids. During prolonged dehydration, the brain detects variations in body fluids and produces sensations of thirst and aversions to salty tastes. At the core of these processes Nax, the brain's Na sensor, exists. Specialized neural nuclei, namely the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which lack the blood--brain barrier, play pivotal roles. Within the glia enveloping the neurons in these regions, Nax collaborates with Na+/K+-ATPase and glycolytic enzymes to drive glycolysis in response to elevated Na levels. Lactate released from these glia cells activates nearby inhibitory neurons. The SFO hosts distinct types of angiotensin II- sensitive neurons encoding thirst and salt appetite, respectively. During dehydration, Nax-activated inhibitory neurons suppress salt-appetite neuron's activity, whereas salt deficiency reduces thirst neuron's activity through cholecystokinin. Prolonged dehydration increases the Na sensitivity of Nax via increased endothelin expression in the SFO. So far, patients with essential hypernatremia have been reported to lose thirst and antidiuretic hormone release due to Naxtargeting autoantibodies. Inflammation in the SFO underlies the symptoms. Furthermore, Nax activation in the OVLT, driven by Na retention, stimulates the sympathetic nervous system via acid-sensing ion channels, contributing to a blood pressure elevation. [ABSTRACT FROM AUTHOR]

Megestrol is commonly used to address appetite loss, cachexia, and significant weight loss in cancer or acquired immune deficiency syndrome patients. This study aimed to assess the pharmacokinetics and determine the bioequivalence of two orally administered megestrol acetate suspensions (625 mg/5 mL) in healthy Korean male subjects. A randomized, open-label, single-dose crossover study was conducted involving fifty-four healthy male subjects who were randomized into two sequence groups. Each subject received either a test or reference drug formulation of 625 mg/5 mL megestrol acetate with a two-week washout period between treatments. Plasma samples were collected before and up to 120 hours after administration, and their plasma drug concentrations were analyzed using validated liquid chromatography–mass spectrometry/mass spectrometry. The pharmacokinetic parameters were calculated, and bioequivalence was confirmed if the 90% confidence intervals of the geometric mean ratios were within the specified bounds of 80.00% to 125.00%. In total, fifty-two subjects completed the study, contributing to the pharmacokinetic analysis. The 90% confidence intervals for the geometric mean ratios of the test formulation compared to the reference formulation were 93.85% to 108.90% for maximum plasma concentration and 91.60% to 101.78% for area under the concentration-time curve from the point of administration to last time point of blood sampling. Throughout the study, no serious or unexpected adverse events were observed. The pharmacokinetic profiles of both formulations of megestrol acetate (625 mg) were comparable and well tolerated in healthy Korean male adult subjects. The test formulation met regulatory criteria for bioequivalence. [ABSTRACT FROM AUTHOR]

5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Purpose: Bariatric surgery remains the most efficient treatment to achieve a sustained weight loss. However, a large proportion of patients experience suboptimal weight loss (SWL). The exact mechanisms involved remain to be fully elucidated, but the homeostatic appetite control system seems to be involved. The aim of this study was, therefore, to compare the plasma concentration of gastrointestinal hormones, and appetite ratings, between those experiencing SWL and optimal weight loss (OWL) after Roux-en-Y gastric bypass (RYGB). Materials and Methods: Fifty participants from the Bariatric Surgery Observation Study (BAROBS) experiencing either SWL or OWL (< or ≥ 50% of excess weight loss (EWL), respectively) > 13 years post-RYGB were compared to 25 non-surgical controls. Plasma concentrations of acylated ghrelin (AG), total glucagon-like peptide-1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK), and subjective ratings of hunger, fullness, desire to eat (DTE), and prospective food consumption (PFC) were assessed in the fasting and postprandial (area under the curve (AUC)) states. Results: Those experiencing OWL presented with higher basal AG and GLP-1 iAUC, and lower AG iAUC compared with SWL and controls. Additionally, both bariatric groups presented with higher PYY and CCK iAUC compared to controls. PFC tAUC was also lower in OWL compared to the SWL group. Total weight loss was positively correlated with GLP-1 tAUC and negatively correlated with fasting and tAUC DTE and PFC tAUC. Conclusions: SWL > 13 years post-RYGB is associated with lower basal ghrelin, as well as a weaker satiety response to a meal. Future studies should investigate the causality of these associations. [ABSTRACT FROM AUTHOR]

This study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP‐induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti‐related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC). The results show CASPASE‐3‐induced ablation of VMN PACAP neurones leads to increased energy intake and meal frequency as well as decreased energy expenditure in lean animals. The effects were more robust in obese males, whereas we saw the opposite effects in obese females. We then utilized visualized whole‐cell patch clamp recordings in hypothalamic slices. PAC1R knockdown in POMC neurones diminishes the PACAP‐induced depolarization, increase in firing, decreases in energy intake and meal size, as well as increases in CO2 production and O2 consumption. Similarly, the lack of expression of the PAC1R in NPY/AgRP neurones greatly attenuates the PACAP‐induced hyperpolarization, suppression of firing, decreases in energy intake and meal frequency, as well as increases in energy expenditure. The PACAP response in NPY/AgRP neurones switched from predominantly inhibitory to excitatory in fasted animals. Finally, the anorexigenic effect of PACAP was potentiated when oestradiol was injected into the ARC in ovariectomized females. This study demonstrates the critical role of anorexigenic VMN PACAP neurones and the PAC1R in exciting POMC and inhibiting NPY/AgRP neurons to control homeostatic feeding. [ABSTRACT FROM AUTHOR]

Objective: To explore the mechanism by which ghrelin regulates insulin sensitivity through modulation of miR-455-5p in hepatic cells. Methods: HepG2 cells were treated with or without DAG (1 µM). Glucose consumption, intracellular glycogen content, phosphorylation of PI3K and Akt stimulated by insulin, expression of miR-455-5p, as well as IGF-1R protein level were analyzed. In addition, bioinformatic analysis, dual luciferase reporter assay, miR-455-5p mimic or inhibitor treatment was conducted to investigate the molecular mechanisms. Results: High glucose treatment upregulated miR-455-5p expression but reduced glucose consumption and glycogen content. DAG reversed the effect of high glucose on glucose metabolism, increased protein level of IGF-1R and phosphorylation of PI3K/Akt stimulated by insulin, as well as downregulated miR-455-5p expression. Bioinformatic analysis indicated IGF-1R was the target of miR-455-5p. Dual luciferase reporter assay, as well as transfection with miR-455-5p mimic/inhibitor confirmed that DAG activated IGF-1R/PI3K/Akt signaling via inhibiting miR-455-5p. Conclusion: DAG improves insulin resistance via miR-455-5pmediated activation of IGF-1R/PI3K/Akt system, suggesting that suppression of miR-455-5p or activation of DAG may be potential targets for T2DM therapy. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) is characterized by emaciation, hyperactivity, and amenorrhea. Imaging studies in AN patients have revealed reductions in grey and white matter volume, which correlate with the severity of neuropsychological deficits. However, the cellular basis for the observed brain atrophy is poorly understood. Although distinct hypothalamic centers, including the arcuate nucleus (ARC) are critically involved in regulating feeding behavior, little is known about potential hypothalamic modifications in this disorder. Since glia e.g. astrocytes and microglia influence neuronal circuits, we investigated the glial changes underlying pathophysiology of starvation in the corpus callosum (CC) and hypothalamus. Female mice were given a limited amount of food once a day and had unlimited access to a running wheel until a 20% weight reduction was achieved (acute starvation). This weight reduction was maintained for two weeks to mimic chronic starvation. Immunohistochemistry was used to quantify the density of astrocytes, microglia, oligodendrocytes, and the staining intensity of neuropeptide Y (NPY), a potent orexigenic peptide. Chronic starvation induced a decreased density of OLIG2+ oligodendrocytes, GFAP+ astrocytes, and IBA1+ microglia in the CC. However, the densities of glial cells remained unchanged in the ARC following starvation. Additionally, the staining intensity of NPY increased after both acute and chronic starvation, indicating an increased orexigenic signaling. Chronic starvation induced glial cell changes in the CC in a mouse model of AN suggesting that glia pathophysiology may play a role in the disease. Plain English Summary: The eating disorder anorexia nervosa (AN) leads to extreme body weight loss, increased physical activity, and the absence of menstrual periods. Studies have revealed reduced brain volumes in patients with AN, which are associated with the severity of cognitive impairments. The cellular basis for this brain volume loss is mostly unclear. Glial cells, recognized for their role as supporting tissue for neuronal cells, may be involved as they can influence neuronal mechanisms. Although distinct brain regions, like the hypothalamus, are critically involved in regulating feeding behavior, little is known about cell changes in that brain region of patients with AN. To investigate these changes, an animal model mimicking the symptoms of AN was used. Glial cell changes in the corpus callosum, which connects the two hemispheres of the brain, were observed. Furthermore, no glial cell changes in the arcuate nucleus of the hypothalamus were obtained. The findings indicate that glial cell changes in the corpus callosum may play a role in the disease. [ABSTRACT FROM AUTHOR]

Cannabinoids are a group of bioactive compounds abundantly present in Cannabis sativa plant. The active components of cannabis with therapeutic potential are known as cannabinoids. Cannabinoids are divided into three groups: plant-derived cannabinoids (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoids. These compounds play a crucial role in the regulation various physiological processes including the immune modulation by interacting with the endocannabinoid system (A complex cell-signaling system). Cannabinoid receptor type 1 (CB1) stimulates the binding of orexigenic peptides and inhibits the attachment of anorexigenic proteins to hypothalamic neurons in mammals, increasing food intake. Digestibility is unaffected by the presence of any cannabinoids in hemp stubble. Endogenous cannabinoids are also important for the peripheral control of lipid processing in adipose tissue, in addition to their role in the hypothalamus regulation of food intake. Regardless of the kind of synaptic connection or the length of the transmission, endocannabinoids play a crucial role in inhibiting synaptic transmission through a number of mechanisms. Cannabidiol (CBD) mainly influences redox equilibrium through intrinsic mechanisms. Useful effects of cannabinoids in animals have been mentioned e.g., for disorders of the cardiovascular system, pain treatment, disorders of the respiratory system or metabolic disorders. Dietary supplementation of cannabinoids has shown positive effects on health, growth and production performance of small and large animals. Animal fed diet supplemented with hemp seeds (180 g/day) or hemp seed cake (143 g/kg DM) had achieved batter performance without any detrimental effects. But the higher level of hemp or cannabinoid supplementation suppress immune functions and reduce productive performance. With an emphasis on the poultry and ruminants, this review aims to highlight the properties of cannabinoids and their derivatives as well as their significance as a potential feed additive in their diets to improve the immune status and health performance of animals. [ABSTRACT FROM AUTHOR]

Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and ß cell mass. We demonstrate that reducing ghrelin -- by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding -- was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and ß cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10-to 12-week-old mice than in 4-week-old mice. Higher ß cell numbers from decreased ß cell apoptosis drove the increase in ß cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the ß cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in ß cells, which supports decreased ß cell apoptosis and/or increased ß cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction is a major pathophysiology observed in hypertension. Ghrelin, a key regulator of metabolism, has been shown to play protective roles in cardiovascular system. However, whether it has the effect of improving endothelial function and lowering blood pressure in Ang II-induced hypertensive mice remains unclear. Methods: In this study, hypertension was induced by continuous infusion of Ang II with a subcutaneous osmotic pumps and ghrelin (30 µg/kg/day) was intraperitoneal injection for 4 weeks. Acetylcholineinduced endothelium-dependent relaxation in aortae was measured on wire myograph and superoxide production in mouse aortae was assessed by fluorescence imaging. Results: We found that ghrelin had protective effects on Ang II-induced hypertension by inhibiting oxidative stress, increasing NO production, improving endothelial function, and lowering blood pressure. Furthermore, ghrelin activated AMPK signaling in Ang II-induced hypertension, leading to inhibition of oxidative stress. Compound C, a specific inhibitor of AMPK, reversed the protective effects of ghrelin on the reduction of oxidative stress, the improvement of endothelial function and the reduction of blood pressure. Conclusions: our findings indicated that ghrelin protected against Ang II-induced hypertension by improving endothelial function and lowering blood pressure partly through activating AMPK signaling. Thus, ghrelin may be a valuable therapeutic strategy for hypertension. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 is a neuromodulatory peptide that regulates the carbohydrate metabolism. It can cross the blood-brain barrier, and, indeed, while mostly produced in the distal small intestine and colon, it is also synthesized in the nucleus of the solitary tract of the brain stem. The wide distribution of glucagon-like peptide 1 receptors in the different areas of the brain is responsible for the pleiotropic effects of glucagon-like peptide 1 in the central nervous system. Notably, the peptide plays important roles in regulating food intake, in memory functioning, as well as in neuroprotective processes and emotions. This makes it an important tool in the treatment of many central nervous system related abnormalities, such as neurodegenerative diseases, addictions and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Many of the drugs used for obesity treatment have adverse effects on the central nervous system. Therefore, novel treatments, such as peripherally acting drugs, are needed. Monoacylglycerol acyltransferase 2 (MGAT2), highly expressed in the small intestine, catalyzes the first step of triacylglycerol re‐synthesis. MGAT2 inhibition suppresses food intake in high‐fat diet (HFD)‐fed mice, but the mechanisms remain unclear. Here, the involvement of the vagus nerve in MGAT2 inhibition‐induced feeding suppression was investigated. Methods: Fasted mice were administered an MGAT2 inhibitor. Food intake was measured after HFD re‐feeding, and the effect of capsaicin pretreatment on changes in food intake was evaluated. The number of c‐fos‐positive cells in the nucleus tractus solitarius and levels of appetite regulators were determined after HFD re‐feeding or lipid gavage. Results: The anorectic effect of the MGAT2 inhibitor was abolished when vagus nerve function was interrupted by capsaicin. MGAT2 inhibition increased the number of c‐fos‐positive cells in the nucleus tractus solitarius and elevated intestinal oleoylethanolamide, plasma peptide tyrosine–tyrosine and plasma glucagon‐like peptide‐1 levels. Conclusion: MGAT2 inhibition suppresses feeding behavior via peripheral vagus nerve signaling and may serve as a novel anti‐obesity strategy with a low risk of unexpected central nervous system‐related adverse effects. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors. Methods: Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice. Results: Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus. Conclusion: This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment. [ABSTRACT FROM AUTHOR]

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The “hunger hormone” ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs. [ABSTRACT FROM AUTHOR]

Background: Ischemia/reperfusion (I/R) injury is a complication of liver transplantation. I/R-induced inflammatory cell death, namely, pyroptosis, that is triggered by overactive inflammasomes results in the production of proinflammatory cytokines. Hepatic I/R injury correlates with the activation of the Caspase-11-mediated pyroptosis pathway. We investigated whether ghrelin, which is a pleiotropic gut hormone, may have anti-hepatic I/R injury effects, but the mechanism by which Ghrelin ameliorates hepatic I/R -induced injury remains a mystery. Methods: Hepatic I/R injury was induced in a mouse model by clamping the left and right lobes of the liver for 90 min followed by reperfusion for 6 h, 12 h, or 24 h. As treatment, a saline with or without ghrelin was infused via the tail vain. Hepatocytes were isolated using a two-step collagenase liver perfusion method. Results: In our study, treatment with ghrelin protected against hepatic I/R injury as shown by decreased alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels (p < 0.001) and reduced the histological injury in liver tissues compared with untreated controls. The LDH level of primary hepatocytes was increased by hypoxia/reoxygenation (H/R), and it was then restored to normal levels by ghrelin-treatment (p < 0.05). Western blotting analysis showed that ghrelin significantly inhibited the expression of pyroptosis-related proteins, including Caspase-11, GSDMD-N, NLRP3 and HMGB1, both in vivo and in vitro (all p < 0.05) compared with the untreated controls. Immunofluorescence showed that the expression of Gasdamin D (GSDMD) in hepatocytes was increased after I/R or H/R, whereas GSDMD expression was reduced by ghrelin treatment (p < 0.05). Conclusions: Our findings suggest that ghrelin ameliorated I/R-induced hepatic injury by inhibiting Caspase-11-mediated pyroptosis. Ghrelin may be a potential therapeutic option to prevent hepatic I/R injury after liver transplantation. [ABSTRACT FROM AUTHOR]

The neurotransmitter acetylcholine (ACh) plays a central role in the regulation of multiple cognitive and behavioral processes, including attention, learning, memory, motivation, anxiety, mood, appetite, and reward. As a result, understanding ACh dynamics in the brain is essential for elucidating the neural mechanisms underlying these processes. In vivo measurements of ACh in the brain have been challenging because of the low concentrations and rapid turnover of this neurotransmitter. Here, we review a number of techniques that have been developed to measure ACh levels in the brain in vivo. We follow this with a deeper focus on use of genetically encoded fluorescent sensors coupled with fiber photometry, an accessible technique that can be used to monitor neurotransmitter release with high temporal resolution and specificity. We conclude with a discussion of methods for analyzing fiber photometry data and their respective advantages and disadvantages. The development of genetically encoded fluorescent ACh sensors is revolutionizing the field of cholinergic signaling, allowing temporally precise measurement of ACh release in awake, behaving animals. Use of these sensors has already begun to contribute to a mechanistic understanding of cholinergic modulation of complex behaviors. [ABSTRACT FROM AUTHOR]

This study is to observe the upregulation effect of astragaloside IV on ghrelin in diabetic cognitive impairment (DCI) rats and to investigate the pathway in prevention and treatment by reducing oxidative stress. The DCI model was induced with streptozotocin (STZ) in conjunction with a high-fat and high-sugar diet and divided into three groups: model, low-dose (40 mg/kg), and high-dose (80 mg/kg) astragaloside IV. After 30 days of gavage, the learning and memory abilities of rats, as well as their body weight and blood glucose levels, were tested using the Morris water maze and then detection of insulin resistance, SOD activity, and serum MDA levels. The whole brain of rats was sampled for hematoxylin–eosin and Nissl staining to observe pathological changes in the hippocampal CA1 region. Immunohistochemistry was used to detect ghrelin expression in the hippocampal CA1 region. A Western blot was used to determine changes in GHS-R1α/AMPK/PGC-1α/UCP2. RT-qPCR was used to determine the levels of ghrelin mRNA. Astragaloside IV reduced nerve damage, increased superoxide dismutase (SOD) activity, decreased MDA levels, and improved insulin resistance. Ghrelin levels and expression increased in serum and hippocampal tissues, and ghrelin mRNA levels increased in rat stomach tissues. According to Western blot, it increased the expression of the ghrelin receptor GHS-R1α and upregulated the mitochondrial function associated-protein AMPK-PGC-1α-UCP2. Astragaloside IV increases ghrelin expression in the brain to reduce oxidative stress and delay diabetes-induced cognitive impairment. It may be related to the promotion of ghrelin mRNA levels. [ABSTRACT FROM AUTHOR]

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1‐36 and PYY3‐36, with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1‐36 and PYY3‐36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux‐en‐Y gastric bypass (RYGB) on fasting and postprandial PYY1‐36 and PYY3‐36 secretion using a newly developed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay. Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1‐36 and PYY3‐36 concentrations. Results: Presurgery, the fasting and postprandial levels of PYY1‐36 and PYY3‐36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1‐36 and PYY3‐36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1‐36 and PYY3‐36, which may account for long‐term differences in efficacy and adverse effects between the two types of surgery. [ABSTRACT FROM AUTHOR]

The article offers information on the physiological roles of adipose tissues, particularly white adipose tissue (WAT) and brown adipose tissue (BAT), in human health and disease. Topics include the impact of excess calories stored in WAT leading to overweight and obesity, and the potential reversal of obesity through a net negative energy balance.

Introduction: Early life ethanol exposure is known to program hypothalamic proopiomelanocortin (POMC) neurons to express a reduced level of POMC and its control of stress axis functions throughout the life span. In this study, we tested whether miRNAs contribute to the ethanol-induced suppression of Pomc gene expression during the developmental period. Methods: In in vivo studies, POMC-EGFP male mice were fed with 2.5 g/kg ethanol using milk formula (AF), pair-fed isocaloric milk formula, or left in the litter during postnatal days (PNDs) 2–6. In in vitro studies, mHypoA-POMC/GFP cells were treated with ethanol (50 mM) for a 24-h period. Hypothalamic tissues or cell extracts were used for measurement of miRNAs and POMC mRNA. Results: Determination of genome-wide microRNA expression profile identified 40 miRNAs significantly altered in hypothalamic tissues of AF mice. In silico analysis further identified miRNA-383, -384, and -488 have putative binding sites at the POMC 3′UTR. However, only miR-383 and miR-384 are identified to be responsive to ethanol. Administration of miR-383 or -384 inhibitor oligos suppressed ethanol-stimulated miR-383 or -384 expression and restored Pomc mRNA and protein expression in AF mice. mHypoA-POMC/GFP cells when treated with ethanol showed elevated levels of miR-383 and miR-384 and reduced level of Pomc mRNA. Treatment with miR-383 or -384 mimic oligos reduced the level of Pomc mRNA, while treatment with miR-383 or -384 inhibitor oligos increased the level of Pomc mRNA. Reporter assay further confirms the binding specificity of miR-383 and miR-384 to Pomc 3'UTR. Conclusion: These data suggest that miR-383 and miR-384 suppress Pomc gene expression and may contribute to the ethanol-induced alteration of the stress axis functions. [ABSTRACT FROM AUTHOR]

Frailty, is a geriatric syndrome that reduces the resistance to stress situations caused by activities of daily living and increases morbidity and mortality. We hypothesized that a decrease in orexigenic peptides or an increase in anorexigenic peptides might be associated with frailty. We aimed to investigate the relationship between frailty and six appetite-related peptides: ghrelin, neuropeptide Y (NPY), agouti-related peptide (AgRP), cocaine-amphetamine-associated peptide (CART), peptide YY, and alpha MSH (α-MSH). This cross-sectional study was conducted on 85 older adults who visited the outpatient clinic. All patients underwent comprehensive geriatric assessment. Frailty status was assessed using the Fried frailty index. Plasma levels of six appetite-related peptides were studied. The mean age was 73.7 ± 5.4 years, 27 (31.8%) of the patients were male, and 32 of the patients (37.6%) were frail. While plasma levels of ghrelin, NPY and AgRP were significantly lower in frail patients, CART and α-MSH levels were higher compared to non-frail patients (p <.05 for all). Peptide YY was found to be higher in the frail group, however, the difference did not reach statistical significance (p =.052). In multivariate logistic regression analysis, the ghrelin, AgRP, CART, and α-MSH levels were independent predictors of frailty. Moreover, a weak correlation was found between all peptides(except NPY) and handgrip strength and Lawton-Brody score. Ghrelin, AgRP, CART, and α-MSH levels were found to be independent predictors of frailty. Our results suggest that appetite-related peptides might be playing roles in the pathogenesis of frailty. Further larger prospective studies are needed to test this hypothesis. [ABSTRACT FROM AUTHOR]

Introduction: Vertical sleeve gastrectomy (VSG) is considered one of the most effective treatments for sustained weight loss and complete remission of type 2 diabetes mellitus (CR-T2DM). Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist peptide, is a metabolic hormone regulated by VSG. However, it is unknown whether LEAP2 can be used to predict the outcomes of VSG. This study aimed to evaluate LEAP2 as a predictive factor for weight loss and CR-T2DM after VSG. Methods: This retrospective study included 39 Japanese participants with obesity who underwent VSG. Serum LEAP2, des-acyl ghrelin (DAG), and other metabolic and anthropometric parameters were studied before and at 12 months after VSG. Receiver operating characteristics (ROC) curve was generated to evaluate predictive score for weight loss with cut-off value of >50 percent excess weight loss. ROC curve was also generated to assess CR-T2DM. Results: Serum LEAP2 levels were significantly higher in participants with body mass index (BMI) 32–50 kg/m2 than in those with normal weight. Participants with BMI >50 kg/m2 had lower serum LEAP2 concentrations than those with BMI 32–50 kg/m2. VSG caused a significant reduction in serum DAG concentrations, but it did not affect serum LEAP2 concentrations in either male or female participants. Preoperative serum LEAP2 concentration of 2.88 pmol/mL was the optimal cutoff value for predicting weight loss after VSG, with sensitivity of 80.0% and specificity of 75.9%. Preoperative serum LEAP2 level higher than 4.67 pmol/mL predicted CR-T2DM after VSG with sensitivity of 100% and specificity of 58.8%. Conclusion: Preoperative serum LEAP2 could predict weight loss and CR-T2DM as outcomes of VSG. [ABSTRACT FROM AUTHOR]

Aims High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic–pituitary–adrenal axis activation and leads to sustained glucocorticoid excess. Methods and results In male C57BL/6 mice, high salt intake for 2–8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic–pituitary–adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic–pituitary–adrenal axis activation by high salt diet. Conclusion Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells. [ABSTRACT FROM AUTHOR]

Introduction: The modern food environment facilitates excessive calorie intake, a major driver of obesity. Glucagon-like peptide 1 (GLP1) is a neuroendocrine peptide that has been the basis for developing new pharmacotherapies against obesity. The GLP1 receptor (GLP1R) is expressed in central and peripheral tissues, and activation of GLP1R reduces food intake, increases the expression of thermogenic proteins in brown adipose tissue (BAT), and enhances lipolysis in white adipose tissue (WAT). Obesity decreases the efficiency of GLP1R agonists in reducing food intake and body weight. Still, whether palatable food intake before or during the early development of obesity reduces the effects of GLP1R agonists on food intake and adipose tissue metabolism remains undetermined. Further, whether GLP1R expressed in WAT contributes to these effects is unclear. Methods: Food intake, expression of thermogenic BAT proteins, and WAT lipolysis were measured after central or peripheral administration of Exendin-4 (EX4), a GLP1R agonist, to mice under intermittent-short exposure to CAF diet (3 h/d for 8 days) or a longer-continuous exposure to CAF diet (24 h/d for 15 days). Ex-vivo lipolysis was measured after EX4 exposure to WAT samples from mice fed CAF or control diet for 12 weeks. Results: During intermittent-short exposure to CAF diet (3 h/d for 8 days), third ventricle injection (ICV) and intra-peritoneal administration of EX4 reduced palatable food intake. Yet, during a longer-continuous exposure to CAF diet (24 h/d for 15 days), only ICV EX4 administration reduced food intake and body weight. However, this exposure to CAF diet blocked the increase in uncoupling protein 1 (UCP1) caused by ICV EX4 administration in mice fed control diet. Finally, GLP1R expression in WAT was minimal, and EX4 failed to increase lipolysis ex-vivo in WAT tissue samples from mice fed CAF or control diet for 12 weeks. Discussion: Exposure to a CAF diet during the early stages of obesity reduces the effects of peripheral and central GLP1R agonists, and WAT does not express a functional GLP1 receptor. These data support that exposure to the obesogenic food environment, without the development or manifestation of obesity, can alter the response to GLP1R agonists. [ABSTRACT FROM AUTHOR]

• Intranasal olanzapine application is a fast and effective delivery method to reduce hyperactivity in the activity-based anorexia model. • Lower doses of mini-pump delivered olanzapine were also effective in reducing hyperactivity in the activity-based anorexia model. • Intranasal olazapine administration in the activity-based anorexia model prevented severe body weight loss. The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzapine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investigated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libitum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue. We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further exploring intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness. [ABSTRACT FROM AUTHOR]

Insulin-like factor 5 (INSL5), a novel hormone secreted by the enteroendocrine cells of the distal colon, has been implicated in appetite and body weight regulation in animals given its orexigenic properties. We investigated basal INSL5 plasma levels in a group of morbidly obese subjects before and after laparoscopic sleeve gastrectomy. Furthermore, we analyzed the expression of INSL5 in human adipose tissue. Before bariatric surgery, obese subjects showed basal INSL5 plasma levels that were positively correlated with BMI, fat mass, and leptin plasma levels. After weight loss by laparoscopic sleeve gastrectomy, INSL5 plasma levels in obese subjects were significantly lower than those observed before surgery. Finally, we did not detect any expression of the INSL5 gene in human adipose tissue, both at the mRNA and protein levels. The present data show that subjects with obesity have INSL5 plasma levels positively correlating with adiposity markers. After bariatric surgery, INSL5 plasma levels decreased significantly, and this decrease was not directly due to the loss of adipose tissue since this tissue does not express INSL5. Considering the orexigenic properties of INSL5, the reduction of its plasma levels after bariatric surgery in obese subjects could participate in the still unclear mechanisms leading to appetite reduction that characterize bariatric surgery procedures. [ABSTRACT FROM AUTHOR]

Cardiometabolic disease is a leading complication of spinal cord injury (SCI) that contributes to premature all-cause cardiovascular morbidity and early death. Despite widespread reports that cardioendocrine disorders are more prevalent in individuals with SCI than those without disability, a well-defined pathophysiology has not been established. Autonomic dysfunction accompanying disruption of autonomic spinal tracts may contribute to dysregulation of energy metabolism via uncoupling of integrated hunger and satiation signals. In governing human feeding behaviors, these signals are controlled by a network of enteroendocrine cells that line the gastrointestinal (GI) tract. These cells regulate GI peptide release and autonomic systems that maintain direct neuroendocrine communication between the GI tract and appetite circuitry of the hypothalamus and brainstem. Here we investigate gene-expression and physiological changes in GI peptides and hormones, as well as changes in physiological response to feeding, glucose and insulin challenge, and evaluate GI tissue cytoarchitecture after experimental SCI. Adult female mice (C57BL/6) were subjected to a severe SCI (65 kDyne) at T9, and a sham control group received laminectomy only. The SCI results in chronic elevation of fasting plasma glucose levels and an exaggerated glucose response after an oral glucose and insulin tolerance test. Mice with SCI also exhibit significant alteration in gut hormone genes, plasma levels, physiological response to prandial challenge, and cell loss and gross tissue damage in the gut. These findings demonstrate that SCI has widespread effects on the GI system contributing to component cardiometabolic disease risk factors and may inform future therapeutic and rehabilitation strategies in humans. [ABSTRACT FROM AUTHOR]

Objective：To discuss the effect of ghrelin on the differentiation of the adipose mesenchymal stem cells (ADSCs) into the neurons, and to clarify its possible mechanism. Methods：The ADSCs were randomly divided into blank group, neural differentiation inducer group, and ghrelin group (given 600 μg·L-1 Ghrelin), U0126 group (given 40 ng·L-1 U0126), Ghrelin+U0126 group (given 600 μg·L-1 Ghrelin+40 ng·L-1 U0126), and Ghrelin receptor blocker D-Lys3-GHRP-6 (D-Lys3-GHRP-6) group (given 10－10 g·L-1 D-Lys3-GHRP-6). The pathomorphology of the cells in various groups was observed under inverted microscope; the positive expression rates of neurofilament protein (NF) -200 and tubulin (Tuj-1) in the cells in various groups were detected by immunofluorescence method; the expression levels of the mitogen activated protein kinase (MAPK) /extracellular signal-regulated kinase (ERK) pathway proteins, neuron specific nuclear protein (NeuN), Tuj-1, neuron specific enolase (NSE), NF, growth hormone secretagogne receptor (GHSR), fetal liver kinase 1 (Flk1), and CD29 proteins in the cells in various groups were detected by Western blotting method. Results：On the 10th day after cell culture, the ADSCs in blank group showed the fusions of long spindle and spiral shapes; the body of the cells in neural differentiation inducer group contracted, and the long spindle like cell body was transformed into the round-like shape, the protrusion length extended, and the number of neuron-like cells was increased; in Ghrelin group, the number of body protrusions of the cells was increased and the number of round-like like cells was increased; there was a small amount of cell body contraction and circular transformation in U0126 group and D-Lys3-GHRP-6 group. The immunofluorescence assay results showed that compared with blank group, the positive expression rates of NF-200 and Tuj-1 in the cells in neural differentiation inducer group were increased (P<0. 05); compared with neural differentiation inducer group, the positive expression rates of NF-200 and Tuj-1 in the cells in Ghrelin group were increased (P<0. 05), while the positive expression rates of NF-200 and Tuj-1 in the cells in U0126 group and D-Lys3-GHRP-6 group were decreased (P<0. 05); compared with Ghrelin group, the positive expression rates of NF-200 and Tuj-1 in the cells in U0126 group, D-Lys3-GHRP-6 group, and Ghrelin+U0126 group were decreased (P< 0. 05). The Western blotting results showed that compared with blank group, the expression levels of NSE, NeuN, Tuj-1, NF, and GHSR proteins, and the ratios of phosphorylated MAPK (p-MAPK) / MAPK and phosphorylated ERK (p-ERK) /ERK in the cells in neural differentiation inducer group were increased (P<0. 05), while the expression levels of Flk1 and CD29 proteins were decreased (P< 0. 05); compared with neural differentiation inducer group, the expression levels of NSE, NeuN, Tuj-1, NF, and GHSR proteins, and the ratios of p-MAPK/MAPK and p-ERK/ERK in the cells in Ghrelin group were increased (P<0. 05), while the expression levels of Flk1 and CD29 proteins were decreased (P< 0. 05); the expression levels of NSE, NeuN, Tuj-1, NF, and GHSR proteins, and the ratios of p-MAPK/ MAPK and p-ERK/ERK in the cells in U0126 and D-Lys3-GHRP-6 groups were decreased (P<0. 05), and the expression levels of Flk1 and CD29 proteins were increased (P<0. 05); compared with Ghrelin group, the expression levels of NSE, NeuN, Tuj-1, NF, and GHSR proteins, and the ratios of p-MAPK/MAPK and p-ERK/ERK in the cells in U0126 group, D-Lys3-GHRP-6 group, and Ghrelin+U0126 group were decreased (P<0. 05), while the expression levels of Flk1 and CD29 proteins were increased (P<0. 05). Conclusion：Ghrelin can induce the differention of the ASCs into the neurons, and it mechanism is related to activating the MAPK/ERK pathway. [ABSTRACT FROM AUTHOR]

Consuming resistant maltodextrin (RMD) decreases food intake and increase appetite-related gut hormones, but the underlying mechanisms have remained unknown. Therefore, we aimed to elucidate the mechanisms underlying the effects of RMD feeding on food intake (appetite) using Institute of Cancer Research male mice fed with a high-fat diet (HFD-cellulose group) or HFD in which cellulose was replaced with RMD (HFD-RMD group). Feeding mice with an HFD-RMD for approximately 8 weeks inhibited excessive calorie intake and altered the gut microbiota composition. Excessive calorie intake was inhibited for several days in mice fed only with an HFD-cellulose and transplanted with fecal microbiota from the HFD-RMD group (FMT-HFD-RMD group). Moreover, in the HFD-RMD and FMT-HFD-RMD groups, serum active glucagon-like peptide (GLP)-1 and peptide tyrosine tyrosine (PYY) levels were significantly higher, and appetite-related neuropeptide gene transcription in the hypothalamus were significantly altered, compared with the HFD-cellulose and FMT-HFD-cellulose groups. These results suggested that the long-term RMD intake changed the gut microbiota composition, increased the GLP-1 and PYY secretion, and altered the appetite-related neuropeptide gene transcription in the hypothalamus, leading to suppressed excessive calorie intake in an HFD. [ABSTRACT FROM AUTHOR]

The article discusses the early weaning-induced obesity and the potential benefits of leucine supplementation in mitigating its effects, with topics including the impact of breastfeeding duration on metabolic health, insights from rodent models, and the mechanisms underlying early weaning-driven obesity. It reports that the study provides new insights into the programming of obesity due to early weaning and suggests the potential of leucine supplementation as a solution to this issue.

Besides enhanced feeding, the orexigenic peptide ghrelin activates the mesolimbic dopamine system to cause reward as measured by locomotor stimulation, dopamine release in nucleus accumbens shell (NAcS), and conditioned place preference. Although the ventral tegmental area (VTA) appears to be a central brain region for this ghrelin-reward, the underlying mechanisms within this area are unknown. The findings that the gaseous neurotransmitter nitric oxide (NO) modulate the ghrelin enhanced feeding, led us to hypothesize that ghrelin increases NO levels in the VTA, and thereby stimulates reward-related behaviors. We initially demonstrated that inhibition of NO synthesis blocked the ghrelin-induced activation of the mesolimbic dopamine system. We then established that antagonism of downstream signaling of NO in the VTA, namely sGC, prevents the ability of ghrelin to stimulate the mesolimbic dopamine system. The association of ghrelin to NO was further strengthened by in vivo electrochemical recordings showing that ghrelin enhances the NO release in the VTA. Besides a GABA B -receptor agonist, known to reduce NO and cGMP, blocks the stimulatory properties of ghrelin. The present series of experiments reveal that ablated NO signaling, through pharmacologically inhibiting the production of NO and/or cGMP, prevents the ability of ghrelin to induced reward-related behaviors. [Display omitted] • Inhibition of nitric oxide (NO) production attenuates ghrelin-induced reward. • Inhibition NO signaling in the ventral tegmental area prevents ghrelin stimulation. • Ghrelin enhances NO release in the ventral tegmental area. • Baclofen, known to reduce NO, blocks the stimulatory properties of ghrelin. [ABSTRACT FROM AUTHOR]

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT6) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT6 agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed. [ABSTRACT FROM AUTHOR]

We evaluated the use of diazepam (Valium®) during the rehabilitation of odontocetes (dolphins and porpoises) to facilitate husbandry and for veterinary purposes, by analyzing detailed records from a period of 14 years of the treatment of 16 stranded individuals: harbor porpoises (Phocoena phocoena), white-beaked dolphins (Lagenorhynchus albirostris), a common dolphin (Delphinus delphis), and a striped dolphin (Stenella coeruleoalba). Diazepam was used occasionally (once per case or for a few days at a time) to facilitate husbandry, including for managing stressful and transitional circumstances and during transport. It was also used occasionally (once per case) for veterinary purposes, such as to reduce stress or to facilitate x-ray scanning, gastroscopy, blood sampling, or wound treatment. Diazepam was found to be effective as an anti-anxiety drug, to cause drowsiness (i.e., reduce activity levels), as a muscle relaxant, and as an appetite stimulant. The doses used were similar for husbandry and veterinary purposes (0.03 to 0.44 mg/kg body weight), and the drug was administered almost exclusively orally (via fish) or via intramuscular injection. [ABSTRACT FROM AUTHOR]

Introduction: Fat mass and obesity-associated (FTO) gene is strongly associated with obesity which brings a major health threat. Altered expression of its encoded protein FTO in the hypothalamus has been identified to contribute to central control of appetite and body weight. However, its molecular mechanisms remain elusive. Methods: Mouse hypothalamic POMC cell line N43/5 was treated with FTO inhibitor rhein, FTO shRNA, or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 to inhibit FTO or ERK1/2. Rhein and U0126 were injected into lateral ventricle of the mice by intracerebroventricular cannulation. Western blotting and immunofluorescent assays were performed to monitor protein level. Results: This study identified that inhibition of FTO in N43/5 cells led to phosphorylation of signal transducer and activator of transcription 3 (STAT3) at S727 site and induced p-STAT3-S727 nuclear translocation. We further showed that FTO inhibition promoted phosphorylation of ERK1/2; specific inhibition of ERK1/2 signaling by U0126 could abolish the effect of FTO inhibition on STAT3-S727 phosphorylation and nuclear translocation. Furthermore, we found that inhibition of hypothalamic FTO promoted STAT3-S727 phosphorylation in the hypothalamic arcuate nucleus, and the mice showed reductions in food intake and body weight. In addition, inhibition of hypothalamic ERK1/2 could abolish the effects of FTO inhibition on STAT3-S727 phosphorylation, reductions of food intake and body weight. Conclusion: Our invitro and invivo data suggest that the inhibition of hypothalamic FTO could activate STAT3 through ERK1/2, which is potentially associated with reductions in food intake and body weight. [ABSTRACT FROM AUTHOR]

The stomach‐derived octanoylated peptide ghrelin was discovered in 1999 and recognized as an endogenous agonist of the growth hormone secretagogue receptor (GHSR). Subsequently, ghrelin has been shown to play key roles in controlling not only growth hormone secretion, but also a variety of other physiological functions including, but not limited to, food intake, reward‐related behaviors, glucose homeostasis and gastrointestinal tract motility. Importantly, a non‐acylated form of ghrelin, desacyl‐ghrelin, can also be detected in biological samples. Desacyl‐ghrelin, however, does not bind to GHSR at physiological levels, and its physiological role has remained less well‐characterized than that of ghrelin. Ghrelin and desacyl‐ghrelin are currently referred to in the literature using many different terms, highlighting the need for a consistent nomenclature. The variability of terms used to designate ghrelin can lead not only to confusion, but also to miscommunication, especially for those who are less familiar with the ghrelin literature. Thus, we conducted a survey among experts who have contributed to the ghrelin literature aiming to identify whether a consensus may be reached. Based on the results of this consensus, we propose using the terms "ghrelin" and "desacyl‐ghrelin" to refer to the hormone itself and its non‐acylated form, respectively. Based on the results of this consensus, we further propose using the terms "GHSR" for the receptor, and "LEAP2" for liver‐expressed antimicrobial peptide 2, a recently recognized endogenous GHSR antagonist/inverse agonist. [ABSTRACT FROM AUTHOR]