Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the ghrelin receptor, countering ghrelin's effects on cell signaling and feeding. However, despite an emerging interest in LEAP2's physiology and pharmacology, its endocrine regulation remains unclear. Here, we report that plasma LEAP2 levels decrease significantly upon glucagon infusions during somatostatin clamps in humans. This effect is preserved in patients with obesity and type 2 diabetes while diminished following a hypercaloric diet and a sedentary lifestyle for 2 weeks. Additionally, insulin receptor antagonism offsets the upregulation of LEAP2 during the postprandial state in mice. Finally, insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression, coinciding with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus. Collectively, our findings implicate insulin and glucagon in regulating LEAP2 and warrant further investigations into the exact mechanisms orchestrating this endocrine axis.

Imbalance between gastrointestinal peptides has been implicated as a cause of chemotherapy-induced nausea and vomiting (CINV) and anorexia in cancer patients. This study comprehensively evaluated the changes in blood levels of five gastrointestinal peptide: substance P, neuropeptide (NPY), motilin, ghrelin and leptin, following chemotherapy, and the relationship between these peptides and CINV or anorexia.

This single-center, prospective, observational study recruited 20 patients with esophageal cancer, urothelial cancer, or testiculoma undergoing cisplatin-based chemotherapy. Plasma levels of five gastrointestinal peptides were measured on days 1 (baseline; before administering chemotherapy), 3, 5 and 8 of the chemotherapy session. Anorexia and CINV were defined as visual analog scale scores 25 mm or higher at least once during the observation period.

Plasma NPY and leptin were significantly elevated in the early phase (day 3) of the chemotherapy session, while plasma motilin and substance P were significantly elevated in the late phase (days 5 and 8). Plasma motilin showed significant elevation on days 5 and 8 compared to baseline in CINV group but no significant increase in non-CINV group, and the levels were significantly higher in CINV than in non-CINV group. Plasma leptin peaked significantly on day 3 in both anorexia and non-anorexia groups, and remained significantly higher on day 5 compared to baseline in anorexia group but not in non-anorexia group.

CINV is associated with excessive secretion of motilin and anorexia is related to sustained elevation of leptin, suggesting the potential of these peptides as quantitative indicators of CINV and anorexia.

Drugs targeting the ghrelin receptor hold therapeutic potential in anorexia, obesity and diabetes. However, developing effective drugs is challenging. To tackle this common issue across a broad drug target, this study aims to understand how anamorelin, the only approved drug targeting the ghrelin receptor, operates compared to other synthetic drugs. Our research elucidated the receptor's structure with anamorelin and miniGq, unveiling anamorelin's superagonistic activity. We demonstrated that ligands with distinct chemical structures uniquely bind to the receptor, resulting in diverse conformations and biasing signal transduction. Moreover, our study showcased the utility of structural information in effectively identifying natural genetic variations altering drug action and causing severe functional deficiencies, offering a basis for selecting the right medication on the basis of the individual's genomic sequence. Thus, by building on structural analysis, this study enhances the foundational framework for selecting therapeutic agents targeting the ghrelin receptor, by effectively leveraging signaling bias and genetic variations.

Migratory birds must accumulate large amounts of fat prior to migration to sustain long flights. In passerines, the small body size limits the amount of energy stores that can be transported, and therefore birds undergo cycles of extreme fattening and rapid exhaustion of reserves. Research on these physiological adaptations was rattled by the discovery that birds have lost the main vertebrate regulator of fat deposition, leptin. Recent studies have thus focused on ghrelin, known as 'hunger hormone', a peptide secreted by the gastrointestinal tract to regulate, e.g. food intake and body mass in vertebrates. Studies on domestic species showed that, in birds, ghrelin has effects opposite to those described in mammals such as inhibiting instead of promoting food intake. Furthermore, recent studies have shown that ghrelin administration influences migratory behaviour in passerine birds. Using comparative genomics and immunoaffinity chromatography, we show that ghrelin has been lost in Eupasseres after the basic split from Acanthisitti about 50 Ma. We found that the ghrelin receptor is still conserved in passerines. The maintenance of a functional receptor system suggests that in Eupasserines, another ligand has replaced ghrelin, perhaps to bypass the feedback system that would hinder the large pre-migratory accumulation of subcutaneous fat.

Ghrelin enhances feeding by activating the growth hormone secretagogue receptor (GHSR). In the brain, GHSRs are expressed in regions responsible for regulating food motivation including the ventral tegmental area (VTA). Endogenous cannabinoids also promote food-seeking behaviors through the cannabinoid receptor-1 (CB-1Rs) in brain regions including the VTA. It is not known, however, if ghrelin and endocannabinoids interact in the VTA to produce these effects. We therefore examined if GHSR and CB-1R interact within the VTA to enhance food motivation. Results show that GHSR and CB-1R mRNA are expressed in the VTA cells in male and female rats and mice, with the GHSR being expressed in dopamine cells and the CB-1R being expressed primarily in nondopaminergic cells with no obvious sex differences. Ghrelin directly activated and increased excitatory tone onto dopamine cells of male and female mice. Male rats lacking fully functional GHSR signaling showed disrupted gene expression of transcripts important for regulating the synthesis, release, and degradation of endocannabinoids and lowered the levels of 2-arachidonoylglycerol (2-AG) within the VTA. Moreover, pharmacological antagonism of VTA CB-1Rs attenuates the orexigenic and appetitive effects of intra-VTA ghrelin in rats and blocks the ability of ghrelin to promote excitatory drive to VTA dopamine neurons. Finally, blocking the breakdown of cannabinoids in the VTA enhances the effects of ghrelin on food motivation. Together, our data show that ghrelin stimulates VTA dopamine cells and ultimately food motivation in part through a mechanism that involves endocannabinoid signaling at the CB-1R.

Anamorelin is a selective ghrelin receptor agonist that is used to treat cancer-related cachexia. Ghrelin stimulates growth hormone (GH) secretion. However, the association between anamorelin and hyperglycemia remains unclear. We herein report a case of anamorelin-induced hyperglycemia in a patient with type 1 diabetes mellitus. A 67-year-old woman with a history of type 1 diabetes was hospitalized because of a pleural effusion. After hospitalization, the patient was administered anamorelin. Four days after starting anamorelin treatment, her blood glucose and GH levels increased. These results suggest that anamorelin stimulates GH secretion and induces hyperglycemia. Our findings suggest the need to take special care of hyperglycemia when anamorelin is prescribed to patients with type 1 diabetes.

Obesity is associated with a decrease in chemosensory perception acuity and increased disease risk, pointing to the need for feasible interventions that affect smell, taste, and cardiometabolic markers. Here, subjects with overweight/obesity are treated with six monthly cycles of a fasting-mimicking diet (FMD) lasting 5 days followed by a normal diet for the rest of the month to determine their effects on chemosensory function and cardiometabolic risk factors. Both arms of the 102 randomized cross-over trial participants indicate FMD-dependent improvements in a wide range of taste and smell chemosensory functions. The portion of hyposmic subjects is reduced from 38.1% at baseline to 6.4% at the end of 6 FMD cycles. FMD cycles also reduce cardiometabolic and inflammatory markers and drug use in diabetic patients. This trial provides evidence for the effect of periodic FMD cycles in improving chemosensory function while reducing cardiometabolic risk factors without requiring long-term lifestyle changes. The trial is registered at ClinicalTrials.gov (NCT04529161).

An eight-week feeding trial was conducted to examine the impact of dietary supplementation with lauric acid (LA) on juvenile black sea bream. A basal diet was formulated containing 19.9% fish meal, while five additional diets were prepared, each supplemented with varying levels of LA: LA1 (0.01%), LA2 (0.02%), LA3 (0.04%), LA4 (0.08%), and LA5 (0.16%), denoted as LA1 through LA5, respectively. Triplicate tanks were randomly allocated to each diet, each containing 20 fish with an initial weight of 1.55 ± 0.02 g. At the conclusion of the trial, the LA3 group exhibited significantly greater final body weight (FBW), weight gain (WG), specific growth rate (SGR), and protein efficiency ratio (PER) compared to the other groups (P < 0.05), while the feed conversion ratio (FCR) was markedly higher in the control group. No significant differences were detected among the groups in terms of initial body weight (IBW), muscle fiber index (MFI), protein productive value (PPV), condition factor (CF), hepatosomatic index (HSI), intraperitoneal fat (IPF), viscerosomatic index (VSI), and survival rate (SR) (P > 0.05). No significant variations were observed among the groups in the proximate compositions of the dorsal muscle and whole body (p > 0.05). Furthermore, no significant differences were observed in serum immune and antioxidant parameters in the midgut and hindgut and digestive enzyme activity (P > 0.05) among the treatment groups. However, the LA3 group demonstrated significantly higher levels of serum immune response markers IgM, C3, and C4 compared to the other groups, while malondialdehyde (MDA) levels were significantly elevated in the control group relative to the others. The LA3 group demonstrated significantly increased fore-intestinal villus height, crypt depth, villus height-to-crypt depth ratio, and goblet cell count per villus compared to the other groups (P < 0.05).

The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.

This systematic review and meta-analysis aimed to examine the effect of Ramadan intermittent fasting on appetite-regulating hormones including leptin, ghrelin, insulin, gastrin, glucagon-like peptide-1, peptide YY, and cholecystokinin.

We searched the MEDLINE, Embase, Cochrane Library, CINAHL, Google Scholar, and Web of Science databases to identify relevant research on appetite-regulating hormones during Ramadan intermittent fasting, published until the end of March 2024.

Data from 16 eligible studies comprising 664 participants (341, 51.4 % male) with a mean ± standard deviation age of 33.9 ± 10.8 years were included. The meta-analysis included 12 studies with complete leptin data, showing no significant effect of Ramadan intermittent fasting on leptin concentrations (standardised mean difference - SMD = -0.11 μg/mL, 95 % CI: -0.36 to 0.14). Analysis of three studies with complete ghrelin data demonstrated a significant increase in ghrelin concentrations following Ramadan intermittent fasting (SMD = 0.31 pg/mL, 95 % CI: 0.03 to 0.60). Six studies examining insulin concentrations pre- and post-fasting revealed no significant effect on insulin concentrations (SMD = -0.24 μU/mL, 95 % CI: -0.54 to 0.02). Similarly, analysis of three studies with complete gastrin data showed no significant effect of intermittent fasting on gastrin concentrations (SMD = 0.23 pg/mL, 95 % CI: -0.71 to 0.99).

Ramadan intermittent fasting significantly increases ghrelin concentrations while showing no significant effects on leptin, insulin, and gastrin. While ghrelin findings were consistent across studies, the high heterogeneity in leptin studies suggests further research to better understand the effects of Ramadan intermittent fasting on appetite-regulating hormones.

Elevated glucocorticoid levels with reduced glucocorticoid responsiveness have been reported in chronic inflammatory conditions. Activation of neurons in the nucleus of the solitary tract by transcutaneous auricular vagus nerve stimulation (taVNS) may activate inhibitory pathways projecting to the hypothalamic paraventricular nucleus (PVN), thus inhibiting corticotropin-releasing hormone (CRH) release and improving glucocorticoid dysfunction in chronic inflammatory conditions. Healthy adults (n = 12) participated in experimental (taVNS) and control (sham-taVNS) sessions at least 4 days apart. A 30-min baseline recording was followed by 30 min of taVNS or sham-taVNS and 40 min of recovery. Ten minutes into taVNS or sham-taVNS, a mental arithmetic stress test (MAST) was conducted for 15 min. The MAST increased heart rate, low frequency (LF) heart rate variability (HRV), and the LF to high frequency ratio of HRV, confirming sympathetic activation. Salivary cortisol levels during the MAST were lower during taVNS (49.5 ± 48.0% from baseline; mean ± SD) compared to sham-taVNS (106.0 ± 81.1% from baseline; mean ± SD; p < 0.05). In a psoriasis patient, daily taVNS for 3 months reduced diurnal salivary cortisol levels from 58.2 ± 35.2 (ng/mL)*h (mean ± SD) to 34.9 ± 13.8 (ng/mL)*h (mean ± SD). While it is possible that taVNS inhibited CRH-releasing neurons in the PVN, our study design did not allow to confirm this potential mechanism.

Whitefish fisheries' side-stream biomass is an abundant underutilized resource that can be valorized to benefit future aquaculture sustainability. Four novel ingredients based on side-streams from Atlantic cod (Gadus morhua) fileting were produced. FM-hb, a fish meal (FM), and FPH-hb, a fish protein hydrolysate based on heads (h) and backbones (b); FM-hbg, a FM based on heads, backbones, and viscera/guts (g); and FPC-g, a fish protein concentrate based on viscera preserved in formic acid. Four diets were prepared containing one of the ingredients replacing 50% of the dietary FM protein, in addition to a positive (FM10) and a negative (FM5) control. The six diets were fed to triplicate tanks with Atlantic salmon (Salmo salar L.; 113 ± 1 g) over 8 weeks. Besides general performance, gut and brain gene expression for selected hormones and key neuropeptides involved in the control of appetite and digestive processes were studied during feeding and postprandial, and possible reference levels for Atlantic salmon were established. All side-stream-added diets performed well, with no significant differences in performance and biometrics between the treatments. Some gene expression differences were observed, but no well-defined patterns emerged supporting clear dietary effects related to digestive performance or appetite. However, in the brain, a short-time upregulation of agouti-related protein-1 (agrp1), corresponded to higher cumulative feed intake (FI) for the FM10 diet supporting notions that this may be a candidate biomarker for appetite in salmon. Expression of stomach ghrelin-1 (ghrl1) was higher than ghrelin-2 (ghrl2) and membrane-bound O-acyltransferase domain-containing 4 (mboat4), and midgut peptide YYa-2 (pyya2) and glucagon-a (gcga) were higher than peptide YYb-1 (pyyb1). A comparison showed that midgut peptide YYa-1 (pyya1), pyya2, and gcga expressions were higher than in the hindgut, which is opposite of what is found in mammals. In conclusion, this study shows that sustainable side-stream raw materials with different characteristics can partly replace high-quality commercial FMs giving similar performance.

Lipids represent the most abundant molecular type in the brain, with a fat content of ∼60% of the dry brain weight in humans. Despite this fact, little attention has been paid to circumscribe the dynamic role of lipids in brain function and disease. Membrane lipids such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid, and endocannabinoids finely regulate both synaptic receptors and ion channels that ensure critical neural functions. After a brief introduction on brain lipids and their respective properties, we review here their role in regulating synaptic function and ion channel activity, action potential propagation, neuronal development, and functional plasticity and their contribution in the development of neurological and neuropsychiatric diseases. We also provide possible directions for future research on lipid function in brain plasticity and diseases.

Due to the growth of aquaculture and the finite supply of fishmeal and oil, alternative marine protein and lipid sources are highly sought after. Particularly promising is the use of side streams from the fish processing industry, allowing for the recovery and retention of otherwise lost nutrients in the food production chain. The aim of the present study was to evaluate the potential of three fish processing side streams as fish feed ingredients. The side streams originated from different stages of the production chain, were used without further processing, and included sprat trimmings (heads, frames, viscera), marinated herring (fillets), and mackerel in tomato sauce (fillets and sauce). The three side streams contained moderate levels of protein (28-32% dry matter) and high levels of lipid (34-43%). The sprat trimmings included ca. 29% ash and 1.5% phosphorous, which may add value due to the high level of essential minerals but needs to be considered in feed formulations. Three diets were formulated to include 50% of each side stream replacing all fishmeal and ca. 80% of the fish oil of the control diet, which contained 35% fishmeal and 10% fish oil. The diets were evaluated in a 12-week feeding trial using rainbow trout (Oncorhynchus mykiss). Fish fed the sprat diet displayed the highest feed intake and growth and showed no negative effects on the intestinal health. The mackerel side stream displayed a good digestibility but resulted in lower growth rates compared to the sprat trimmings. Fish fed the herring diet displayed the lowest performance regarding growth, feed intake, and digestibility. They further exhibited a reduction in nutrient uptake in both proximal and distal intestines, likely contributing to the observed lower digestibility and growth, and a reduction in plasma ghrelin levels. As part of a circular approach to increase marine lipid and protein production for fish feed, the tested sprat and mackerel side streams are promising raw materials; however, additional studies using more commercial-like feed formulations are encouraged.

Background/Objectives: Endothelial peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipose tissue by facilitating lipid uptake into white adipocytes, but the role of endothelial lipid transport in systemic energy balance remains unclear. Ghrelin conveys nutritional information through the central nervous system and increases adiposity, while deficiency in its receptor, growth hormone secretagogue-receptor (GHSR), suppresses adiposity on a high-fat diet. This study aims to examine the effect of ghrelin/GHSR signaling in the endothelium on lipid metabolism. Methods: We compared the effects of ghrelin on adiposity and lipid uptake into adipocytes in wild-type and GHSR-null mice. Transgenic mice expressing GHSR selectively in endothelial cells were also generated and compared with global GHSR-null and wild-type mice. The impact of ghrelin on lipid uptake-related genes was assessed in cultured endothelial cells. Results: Ghrelin increased adiposity and triglyceride clearance in wild-type but not in GHSR-null mice. GHSR-null mice showed higher serum triglyceride after olive oil gavage and lower white adipose tissue (WAT) weight on a high-fat diet, suggesting impaired lipid uptake. Restoring GHSR expression in endothelial cells increased lipoprotein lipase activity, lipid uptake into WAT, and WAT weight. Ghrelin enhanced free fatty acid uptake and the expression of lipid uptake genes in cultured endothelial cells, whereas these effects were absent in GHSR-null mice-derived endothelial cells. Knockdown of PPARγ revealed that ghrelin/GHSR signaling in endothelial cells promoted lipid uptake via endothelial PPARγ. Conclusions: Endothelial GHSR is key for regulating lipid metabolism via PPARγ in response to ghrelin and for the role of endothelium in regulating white adipocyte metabolism. Targeting endothelial ghrelin signaling may be a promising therapeutic approach for managing excessive adiposity and associated metabolic disorders.

BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.

This paper provides a critical overview on GHRH and its deficiency, discussing its multiple roles in both central and peripheral tissues. Genetically engineered mice have been instrumental in elucidating the multifaceted roles of GHRH and GH, each offering unique insights into the physiological and pathological roles of these hormones, although in many of these models dissecting the direct effect of GHRH from the effect of GH is not possible. Key findings highlight the effects of GHRH deficiency on emotional behavior, including anxiety and depression, its impact on memory and learning capabilities, as well as on adipose tissue, immune system, inflammation and pain.

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

The regulation of growth hormone (GH) synthesis and secretion by somatotroph cells of the anterior pituitary is a highly complex process, mediated by a variety of neuroendocrine and peripheral influences. In particular, a key role is played by the hypothalamic peptides growth hormone-releasing hormone (GHRH) and somatostatin, which regulate the somatotroph axis with opposite actions, stimulating and inhibiting GH release, respectively. Since the discovery of GHRH about 50 years ago, many pathophysiological studies have explored the underlying intricate hormonal balance that regulates GHRH secretion and its interplay with the somatotroph axis. Various molecules and pathophysiological states have been shown to modulate the release of GH, GHRH, somatostatin and GH secretagogues. Collectively, the available evidence demonstrates how a vast number of neural and peripheral signals are conveyed and integrated to orchestrate a finely tuned response of the somatotroph axis that adapts to the body's varying needs for growth, metabolism, and repair. The present review aims to summarize the available evidence regarding the key regulators involved in the modulation of the somatotroph axis in humans, presenting detailed molecular insights on the signaling cascades at play. The interplay between different mechanisms governing somatotroph secretion is highlighted, underscoring the nuanced interdependence that maintains homeostasis and facilitates the body's ability to respond to internal and external stimuli.

Whether gastrointestinal hormones in patients with postprandial distress syndrome (PDS) are altered by acupuncture, and whether such alterations are related to the autonomic nervous system (ANS), remains an open question.

This study aims to investigate the effects of acupuncture on symptoms, serum hormones, and ANS in PDS patients.

This randomized controlled clinical trial was conducted at Beijing Hospital of Traditional Chinese Medicine affiliated with Capital Medical University. Sixty-two PDS patients were randomly assigned equally to acupuncture or sham acupuncture arm (3 sessions per week for 4-week). The main outcome measures which were evaluated at baseline and 4-week included cardinal symptoms, serum hormones including ghrelin, vasoactive intestinal peptide (VIP), substance P (SP), and ANS.

Among the 62 randomly assigned participants, 51 (82%) were included in the baseline characteristics and outcome analysis. Gastrointestinal symptoms including response rate (p = 0.001) and dyspepsia symptom severity (p = 0.002) were significantly improved after acupuncture treatment. Serum ghrelin concentration was significantly higher in acupuncture group than in sham acupuncture group (8.34 ± 3.00 ng/ml versus 6.52 ± 2.00 ng/ml, p = 0.022) after 4-week treatment, instead of VIP and SP (p > 0.05). The acupuncture group had significantly higher vagal activity, showing with increasing of high-frequency component (HF, p ≤ 0.001) and decreasing of the ratio of low-frequency and HF (p ≤ 0.001). In relationship analysis, the HF component exhibited a significant inverse correlation with symptom severity (R = - 0.501, p ≤ 0.001), but not with ghrelin level (R = 0.026, p = 0.865).

Acupuncture may improve the symptoms and increase the ghrelin level of PDS patients, the therapeutic effect of acupuncture was associated with the alteration of vagal activity.

The trial is registered with the ISRCTN registry, ISRCTN12511434. Registered 31 March 2017, https://www.isrctn.com/ .

Quantitative analysis of peptides in biological fluids offers a high diagnostic and prognostic tool to reflect the pathophysiological condition of the patient. Recently, methods based on liquid chromatography coupled with mass spectrometry (LC-MS) for the quantitative determination of intact peptides have been replacing traditionally used ligand-binding assays, which suffer from cross-reactivity issues. The use of "top-down" analysis of peptides is rapidly increasing since it does not undergo incomplete or non-reproducible digestion like "bottom-up" approaches. However, the low abundance of peptides and their peculiar characteristics, as well as the complexity of biological fluids, make their quantification challenging. Herein, the analytical pitfalls that may be encountered during the development of an LC-MS method for the analysis of intact peptides in biological fluids are discussed. Challenges in the pre-analytical phase, stability after sampling and sample processing, significantly impact the accuracy of peptide quantification. Emerging techniques, such as microextractions, are becoming crucial for improved sample cleanup and enrichment of target analytes. A comparison between the roles of high-resolution and low-resolution mass spectrometry in the quantification of intact peptides, as well as the introduction of supercharging reagents to enhance ionization, will be discussed.

The endocrine control of food intake remains incompletely understood, and whether the leptin receptor (LepR)-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here, we identify an appetite-stimulating factor - ASRA - that represents a peripheral signal of energy deficit and orthosterically antagonizes LepR signaling. Asra encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver. ASRA associates with autophagy vesicles and its secretion is enhanced by energy deficiency. In vivo, fasting and cold stimulate Asra expression and increase its protein concentration in cerebrospinal fluid. Asra overexpression attenuates LepR signaling, leading to elevated blood glucose and development of severe hyperphagic obesity. Conversely, either adipose- or liver-specific Asra knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, resistance to high-fat diet-induced obesity, and blunted cold-evoked feeding response. Mechanistically, ASRA acts as a high affinity antagonist of LepR. AlphaFold2-multimer prediction and mutational studies suggest that a core segment of ASRA binds to the immunoglobin-like domain of LepR, similar to the 'site 3' recognition of the A-B loop of leptin. While administration of recombinant wild-type ASRA protein promotes food intake and increases blood glucose in a LepR signaling-dependent manner, point mutation within ASRA that disrupts LepR-binding results in a loss of these effects. Our studies reveal a previously unknown endocrine mechanism in appetite regulation and have important implications for our understanding of leptin resistance.

Obesity is a complex, multifactorial condition involving excessive fat accumulation due to an imbalance between energy intake and expenditure, with its global prevalence steadily rising. This condition significantly increases the risk of chronic diseases, including sarcopenia, type 2 diabetes, and cardiovascular diseases, highlighting the need for effective interventions. Exercise has emerged as a potent non-pharmacological approach to combat obesity, targeting both central and peripheral mechanisms that regulate metabolism, energy expenditure, and neurological functions. In the central nervous system, exercise influences appetite, mood, and cognitive functions by modulating the reward system and regulating appetite-controlling hormones to manage energy intake. Concurrently, exercise promotes thermogenesis in adipose tissue and regulates endocrine path-ways and key metabolic organs, such as skeletal muscle and the liver, to enhance fat oxidation and support energy balance. Despite advances in understanding exercise's role in obesity, the precise interaction between the neurobiological and peripheral metabolic pathways remains underexplored, particularly in public health strategies. A better understanding of these interactions could inform more comprehensive obesity management approaches by addressing both central nervous system influences on behavior and peripheral metabolic regulation. This review synthesizes recent insights into these roles, highlighting potential therapeutic strategies targeting both systems for more effective obesity interventions.

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell-specific deficiency of Piezo1 (Ghrl-Piezo1-/-) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1-/- mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1-/- mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.

Liver-expressed antimicrobial peptide 2 (LEAP2) is a peptide that counteracts the hunger hormone ghrelin-induced functions. Recently, we showed that vertical sleeve gastrectomy (VSG) did not alter the serum LEAP2 concentration in individuals with obesity. Here, we investigated the effects of VSG in both chow diet (CD)-fed and high-fat diet (HFD)-fed mice. In CD-fed mice, VSG increased plasma LEAP2 levels and hepatic Leap2 mRNA levels while decreasing body weight, blood glucose levels, and ghrelin levels. Intraperitoneal (ip) administration of ghrelin reversed these changes. These effects were found in both male and female mice. In contrast, VSG or weight loss in HFD-induced obese mice decreased LEAP2 levels. After fasting, the plasma LEAP2 concentration was in the following order: hepatic vein > abdominal aorta > portal vein. A high glucose concentration robustly increased the plasma LEAP2 concentration in the hepatic vein and abdominal aorta but not in the portal vein. In addition, corn oil or palmitate increased LEAP2 expression and secretion. The increase in LEAP2 levels after the meal tolerance test was delayed in the human subjects with diabetes. Our data suggest that various factors (metabolic, hormonal, and nutritional) regulate LEAP2, and the liver is the predominant site for the production and secretion of LEAP2. Furthermore, the interaction between ghrelin and LEAP2 is involved in the pathogenesis of obesity and diabetes.

Daily torpor is an active hypothermic phenomenon that is observed in some mammals and birds during fasting. A decrease in blood pressure has also been observed in torpor; however, there remains a lack of knowledge of the underlying mechanism. We have previously reported that ghrelin, an orexigenic hormone, has a hypothermic effect and is essential for the induction and maintenance of torpor. It is also known that the ghrelin secretion is enhanced during fasting and that ghrelin receptors are distributed in the cardiovascular system. Therefore, this study was conducted to test the hypothesis that ghrelin is actively involved in the regulation of blood pressure during torpor induction.

Male wild-type and ghrelin gene-deficient mice were generated by homologous recombination as previously reported. Mice, 10 weeks old, were included in this study and housed five per cage. The mice were maintained on a 12-h light/dark cycle (lights on from 7:00 to 19:00) with access to food and water ad libitum.

The continuous measurement of blood pressure using a telemetry system showed that induction of torpor by fasting did not decrease blood pressure in ghrelin gene-deficient mice. The analysis of heart rate variability revealed that sympathetic nerve activity was predominant in ghrelin-deficient mice during fasting. Furthermore, these features were cancelled by administration of a ghrelin receptor agonist and were comparable to those in wild-type mice.

In this study, we showed that blood pressure was elevated in ghrl-/- mice and that the blood pressure rhythm was abnormal. Furthermore, we showed that the ghrelin gene deficiency does not cause sufficient blood pressure reduction upon entry into the torpor, and that the administration of the ghrelin receptor agonist, GHRP-6, causes blood pressure reduction associated with torpor. Thus, we have shown for the first time that the active role of ghrelin is essential for active blood pressure reduction associated with torpor, and that this action is mediated by the inhibition of sympathetic nerve activity by ghrelin.

An imbalance between energy intake and energy expenditure predisposes obesity and its related metabolic diseases. Soluble dietary fiber has been shown to improve metabolic homeostasis mainly via microbiota reshaping. However, the application and metabolic effects of insoluble fiber are less understood. Herein, we employed nanotechnology to design citric acid-crosslinked carboxymethyl cellulose nanofibers (CL-CNF) with a robust capacity of expansion upon swelling. Supplementation with CL-CNF reduced food intake and delayed digestion rate in mice by occupying stomach. Besides, CL-CNF treatment mitigated diet-induced obesity and insulin resistance in mice with enhanced energy expenditure, as well as ameliorated inflammation in adipose tissue, intestine and liver and reduced hepatic steatosis, without any discernible signs of toxicity. Additionally, CL-CNF supplementation resulted in enrichment of probiotics such as Bifidobacterium and decreased in the relative abundances of deleterious microbiota expressing bile salt hydrolase, which led to increased levels of conjugated bile acids and inhibited intestinal FXR signaling to stimulate the release of GLP-1. Taken together, our findings demonstrate that CL-CNF administration protects mice from diet-induced obesity and metabolic dysfunction by reducing food intake, enhancing energy expenditure and remodeling gut microbiota, making it a potential therapeutic strategy against metabolic diseases.

Weight loss (WL) after gastrectomy for gastric cancer is associated with both decreased compliance with adjuvant chemotherapy and impaired survival. This study examined the effects of administering oral nutritional supplements (ONS) for 3 months after gastrectomy in terms of compliance with adjuvant chemotherapy and survival outcomes.

This large-scale, multicenter, open-label, randomized controlled trial enrolled 1,003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the control group (n = 503) or ONS group (n = 500). In the ONS group, 400 kcal/day of ONS was recommended in addition to a regular diet for 3 months after gastrectomy. Compliance with adjuvant chemotherapy and survival outcomes were compared between the two groups.

Compared with the control group, the ONS group showed significantly decreased WL at 3 months after gastrectomy (8.6 ± 6.1 vs. 7.2 ± 5.7%, respectively, P = 0.0004). The control and ONS groups did not differ regarding the induction rate of adjuvant chemotherapy (84.9 vs. 82.8%, respectively, P = 0.614) or the continuation rate at 3 months postoperatively (75.3 vs. 76.6%, respectively, P = 0.809). Oral nutritional supplements for 3 months showed no survival benefit; the 3- and 5-year overall survival (OS) rates were 91.3% and 87.6% in the control group and 89.6% and 86.4% in the ONS group, respectively, indicating no significant difference (P = 0.548). Subgroup analysis could not detect a population in which ONS administration increased OS.

Administration of ONS for 3 months after gastrectomy was not associated with increased compliance with adjuvant chemotherapy or with improved prognosis.

The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.

Fescue toxicosis is a syndrome occurring from the consumption of endophyte-infected tall fescue and results in substantial economic losses to the beef industry primarily from reduced growth accompanied by decreased dry matter intake (DMI); however, the associations characterizing this reduction in DMI have yet to be elucidated. The objective of this experiment was to identify endocrine changes associated with intake regulation post-consumption of endophyte-infected tall fescue seed (E+). Twelve Holstein steers were stratified by body weight and assigned to 1 of 3 treatments (n=4): 0 ppm ergovaline (ERV), 1.8 ppm ERV, or 2.7 ppm ERV. Treatments were achieved by combining differing proportions of ground E+ and non-endophyte-infected tall fescue seed. Steers were adapted to their diets for 7 d followed by a 7 d DMI collection period. Within treatment, steers were assigned to a sampling day (d 16 or d 17). Blood samples were collected every 20 min for 8 h, beginning 1 h before feeding. Intake data was analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC) with treatment, day, and the interaction as fixed effects. Hormone and metabolite data were analyzed with the fixed effect of treatment, time, and the interaction including time as a repeated measure and orthogonal contrasts. Dry matter intake was linearly decreased with increasing ERV in the diet (P < 0.001). Insulin and leptin concentrations exhibited a quadratic effect (P = 0.018 and P = 0.005) with insulin concentrations highest for the 2.7 ppm treatment and leptin concentrations highest for the 1.8 ppm treatment. No differences were detected for active ghrelin or β-hydroxybuytrate concentrations among treatment groups. Further, steers consuming both the 1.8 and 2.7 ppm ERV treatments had lower prolactin concentrations compared to the 0 ppm treatment (quadratic, P= 0.019). Glucose concentrations had a tendency for a linear increase as ERV concentrations increased (P = 0.091). A treatment × time interaction (P = 0.002) was noted in NEFA concentrations, with the 1.8 ppm ERV treatment showing increased pre-feeding concentrations, and the 2.7 ppm ERV treatment exhibiting elevated NEFA concentrations as time post-feeding progressed. The results suggest that E+ consumption reduces intake likely through alterations in intake-related hormones and post-absorptive metabolism and contributes to our current understanding of E+ effects on intake reduction while providing avenues for future research.

As a classical traditional Chinese medicine formula to invigorating spleen and replenishing qi, Sijunzi decoction (SJZD) is composed of four herbs, which is applied to cure spleen deficiency syndrome (SDS) clinically. The non-polysaccharides (NPSs) of SJZD (SJZD_NPS) are important pharmacodynamic material basis. However, the amelioration mechanism of SJZD_NPS on SDS has not been fully elaborated. Additionally, the contribution of herbs compatibility to efficacy of this formula remains unclear.

The aim was to explore the underlying mechanisms of SJZD_NPS on improving SDS, and uncover the scientific connotation in SJZD compatibility.

A strategy integrating incomplete formulae (called "Chai-fang" in Chinese) comparison, pharmacodynamics, gut microbiome, and metabolome was employed to reveal the role of each herb to SJZD compatibility against SDS. Additionally, the underlying mechanism harbored by SJZD_NPS was further explored through targeted metabolomics, network pharmacology, molecular docking, pseudo-sterile model, and metagenomics.

SJZD_NPS significantly alleviated diarrhea, disordered secretion of gastrointestinal hormones and neurotransmitters, damage of ileal morphology and intestinal barrier in SDS rats, which was superior to the NPSs of Chai-fang. 16S rRNA gene sequencing and metabolomics analyses revealed that SJZD_NPS effectively restored the disturbed gut microbiota community and abnormal metabolism caused by SDS, showing the most evident recovery. Moreover, SJZD_NPS recalled the levels of partial amino acids, short chain fatty acids and bile acids, which possessed strong binding affinity towards potential targets. The depletion of gut microbiota confirmed that the SDS-amelioration efficacy of SJZD_NPS is dependent on the intact gut microbiome, with the relative abundance of potential probiotics such as Lactobacillus_johnsonii and Lactobacillus_taiwanensis been enriched.

NPSs in SJZD can improve SDS-induced gastrointestinal-nervous system dysfunction through regulating microbiota-gut-metabolites axis, with four herbs exerting synergistic effects, which indicated the compatibility rationality of SJZD.

Addressing the shortage of high-quality protein resources, this study was conducted to investigate the effects of replacing soybean meal (SBM) with different levels of enzymolysis-fermentation compound protein feed (EFCP) in the diets of growing-finishing pigs, focusing on growth performance, nutrients digestibility, carcass traits, and meat quality.

Sixty DLY (Duroc × Landrace × Yorkshire) pigs with an initial body weight of 42.76 ± 2.05 kg were assigned to 5 dietary treatments in a 2 × 2 + 1 factorial design. These dietary treatments included a corn-soybean meal diet (CON), untreated compound protein feed (UCP) substitution 50% (U50) and 100% SBM (U100) diets, and EFCP substitution 50% (EF50) and 100% SBM (EF100) diets. Each treatment had 6 pens (replicates) with 2 pigs per pen, and the experiment lasted 58 d, divided into phase I (1-28 d) and phase II (29-58 d). Following phase I, only the CON, U50, and EF50 groups were continued for phase II, each with 5 replicate pens. On d 59, a total of 15 pigs (1 pig/pen, 5 pens/treatment) were euthanized.

During phase I, the EF50 group had a higher average daily gain (ADG) in pigs (P < 0.05) compared to the CON group, whereas the U50 group did not have a significant difference. As the substitution ratio of UCP and EFCP increased in phase I, there was a noticeable reduction in the final body weight and ADG (P < 0.05), along with an increase in the feed-to-gain ratio (F/G) (P < 0.05). In phase II, there were no significant differences in growth performance among the treatment groups, but EF50 increased the apparent digestibility of several nutrients (including dry matter, crude protein, crude fiber, acid detergent fiber, ash, gross energy) compared to U50. The EF50 group also exhibited significantly higher serum levels of neuropeptide Y and ghrelin compared to the CON and U50 groups (P < 0.05). Moreover, the EF50 group had higher carcass weight and carcass length than those in the CON and U50 groups (P < 0.05), with no significant difference in meat quality.

The study findings suggest that replacing 50% SBM with EFCP during the growing-finishing period can improve the growth performance, nutrient digestibility, and carcass traits of pigs without compromising meat quality. This research offers valuable insights into the modification of unconventional plant protein meals and developing alternatives to SBM.

Ghrelin, a peptide found in the brain and gut, is predicted to play a significant role in the control of various physiological systems in fish. The objective of this study was to examine the impact of ipamorelin acetate (IPA), a ghrelin agonist, on the reproductive axis of the tilapia Oreochromis mossambicus. The administration of either 5 or 30 µg of IPA for 21 days led to a significant and dose-dependent rise in food intake concomitant with a significant increase in the numbers of primary spermatocytes, secondary spermatocytes, and early spermatids compared to the control group. There was a significant rise in the number of late spermatids, as well as the areas of the lobule and lumen, in fish treated with 30 µg of IPA, compared to the control group. Moreover, there was no significant difference in the percentage of gonadotropin-releasing hormone (GnRH)-immunoreactive fibres in the hypothalamus and anterior pituitary gland across different groups. However, a significant elevation in the expression of androgen receptor protein was observed in fish treated with 30 µg of IPA. Furthermore, the concentrations of luteinizing hormone (LH) and 11-ketotestosterone (11-KT) in the serum of fish treated with either 5 or 30 µg of IPA were significantly elevated in comparison to the control group. Collectively, these findings suggest that the administration of ghrelin enhances the development of germ cells during the meiosis-I phase and that this effect might be mediated via the stimulation of 11-KT and androgen receptors at the testicular level and LH at the pituitary level in the tilapia.

Investigating the principles of fish fat deposition and conducting related research are current focal points in fish nutrition. This study explores the endocrine regulation of LEAP2 and GHSR1a in zebrafish by constructing mutantmodels andexamining the effects of the endocrine factors LEAP2 and its receptor GHSR1a on zebrafish growth, feeding, and liver fat deposition. Compared to the wild type (WT), the mutation of LEAP2 results in increased feeding and decreased swimming in zebrafish. The impact is more pronounced in adult female zebrafish, characterized by increased weight, length, width, and accumulation of lipid droplets in the liver.Incontrast, deficiency in GHSR1a significantly reduces the growth of male zebrafish and markedly decreases liver fat deposition.These research findings indicate the crucial roles of LEAP2 and GHSR1a in zebrafish feeding, growth, and intracellular fat metabolism. This study, for the first time, investigated the endocrine metabolic regulation functions of LEAP2 and GHSR1a in the model organism zebrafish, providing initial insights into their effects and potential mechanisms on zebrafish fat metabolism.

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

Ghrelin, a peptide primarily secreted in the stomach, acts via the growth hormone secretagogue receptor (GHSR). It regulates several physiological processes, such as feeding behavior, energy homeostasis, glucose and lipid metabolism, cardiovascular function, bone formation, stress response, and learning. GHSR exhibits significant expression within the central nervous system. However, numerous murine studies indicate that ghrelin is limited in its ability to enter the brain from the bloodstream and is primarily confined to specific regions, such as arcuate nucleus (ARC) and median eminence (ME). Nevertheless, the central ghrelin system plays an essential role in regulating feeding behavior. Furthermore, the role of vagal afferent fibers in regulating the functions of ghrelin remains a major topic of discussion among researchers. In recent times, numerous studies have elucidated the substantial therapeutic potential of ghrelin in most gastrointestinal (GI) diseases. This has led to the development of numerous pharmaceutical agents that target the ghrelin system, some of which are currently under examination in clinical trials. Furthermore, ghrelin is speculated to serve as a promising biomarker for GI tumors, which indicates its potential use in tumor grade and stage evaluation. This review presents a summary of recent findings in research conducted on both animals and humans, highlighting the therapeutic properties of ghrelin system in GI disorders.

Liver-expressed antimicrobial peptide 2 (LEAP-2) has been recently identified as the endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). In rodents, LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status, being decreased upon fasting and increased in high-fat diet (HFD) fed mice. Clinical data support the regulation of circulating LEAP-2 by nutrient availability in humans. In this work, our primary objective was to examine the chronic effects of ghrelin and LEAP-2 administration on food intake, adiposity, and energy expenditure in young mice subjected to standard and HFD at both room temperature and at thermoneutrality. Furthermore, we aimed to assess the impact of these two hormones on aging mice.

Our results indicate that LEAP-2 produces a significant decrease of body weight and adiposity, an increase in energy expenditure, and activation of the thermogenic program in white and brown adipose tissue depots. However, this effect is not maintained under HFD or under thermoneutral conditions and is only partially observed in aging mice.

In summary our studies describe the central effects of LEAP-2 within distinct experimental contexts, and contribute to the comprehension of LEAP-2's role in energy metabolism.

The central nucleus of the amygdala (CeA) is part of the dopaminergic reward system and controls energy balance. Recently, a cluster of neurons was identified as responsive to the orexigenic effect of ghrelin and fasting. However, the signaling pathway by which ghrelin and fasting induce feeding is unknown. AMP-activated protein kinase (AMPK) is a cellular energy sensor, and its Thr172 phosphorylation (AMPKThr172) in the mediobasal hypothalamus regulates food intake. However, whether the expression and activation of AMPK in CeA could be one of the intracellular signaling activated in response to ghrelin and fasting eliciting food intake is unknown.

To evaluate the activation of AMPK into CeA in response to ghrelin, fasting, and 2-deoxy-D-glucose (2DG) and whether feeding accompanied these changes. In addition, to investigate whether the inhibition of AMPK into CeA could decrease food intake.

On a chow diet, eight-week-old Wistar male rats were stereotaxically implanted with a cannula in the CeA to inject several modulators of AMPKα1/2Thr172 phosphorylation, and we performed physiological and molecular assays.

Fasting increased, and refeeding reduced AMPKThr172 in the CeA. Intra-CeA glucose injection decreased feeding, whereas injection of 2DG, a glucoprivation inductor, in the CeA, increased food intake and blood glucose, despite faint increases in AMPKThr172. Intra-CeA ghrelin injection increased food intake and AMPKThr172. To further confirm the role of AMPK in the CeA, chronic injection of Melanotan II (MTII) in CeA reduced body mass and food intake over seven days together with a slight decrease in AMPKThr172.

Our findings identified that AMPK might be part of the signaling machinery in the CeA, which responds to nutrients and hormones contributing to feeding control. The results can contribute to understanding the pathophysiological mechanisms of altered feeding behavior/consumption, such as binge eating of caloric-dense, palatable food.