Search Results (178)

Purpose: Acute exercise elicits coordinated neuroendocrine and autonomic responses that are strongly influenced by exercise modality and intensity. While cortisol and salivary alpha-amylase are widely used as peripheral indicators of hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system activation, respectively, salivary orexin remains an exploratory biomarker whose relationship with central orexinergic activity is not yet fully established, particularly in response to different exercise conditions. This study aimed to compare the acute salivary responses of orexin, alpha-amylase, and cortisol following distinct exercise modalities characterized by different physiological loads. Methods: A repeated-measures design was employed in a sample of physically active young women. Each participant completed four experimental sessions: high-intensity interval training (HIIT), combined exercise (CE), moderate-intensity continuous training (MICT), and yoga. Saliva samples were collected at baseline (T0), immediately post-exercise (T1), and during early recovery (T2 and T3). Biomarker concentrations were analyzed to assess temporal dynamics and modality-dependent differences. Results: All biomarkers showed modality-dependent responses. HIIT elicited the most pronounced increases in alpha-amylase and cortisol, reflecting robust sympathetic and HPA axis activation, whereas CE and MICT induced more moderate responses. Yoga was associated with minimal changes across all biomarkers. Orexin displayed a graded response across the exercise modalities, with higher post-exercise levels observed following HIIT compared to lower-intensity conditions. Temporal analyses revealed distinct kinetic profiles, with alpha-amylase peaking rapidly in the early post-exercise phase, whereas cortisol exhibited a more delayed response. Conclusions: These findings demonstrate that acute salivary responses of orexin, alpha-amylase, and cortisol are strongly modulated by exercise modality, supporting the importance of an integrated, multi-biomarker approach to characterize the physiological response to exercise. The inclusion of salivary orexin provides exploratory information on a potentially relevant arousal- and energy-regulation-related pathway, complementing established peripheral markers of autonomic and endocrine activation. This integrated perspective may contribute to a more comprehensive understanding of exercise-induced stress responses in young women. Full article

Insomnia is a common sleep disorder that significantly impairs quality of life and increases the risk of various chronic diseases. Although conventional sedative–hypnotic agents are effective, their clinical use is limited by tolerance, dependence, and residual next-day effects. The orexin system plays a critical role in sleep–wake regulation through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), with OX2R serving as the primary mediator of wakefulness. Based on this mechanism, orexin receptor antagonists (ORAs) have been developed to promote sleep by suppressing wake-promoting signaling pathways. This review systematically summarizes the structural and functional characteristics of the orexin system, with particular emphasis on the functional divergence of OX1R and OX2R and their therapeutic relevance. Recent advances in dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists are discussed, and the pharmacological properties and clinical performance of approved and investigational agents are compared. In addition, the safety profiles, adverse effects, and clinical limitations of ORAs are reviewed. Future perspectives are highlighted, including receptor selectivity, pharmacokinetic optimization, and personalized treatment strategies. Collectively, ORAs offer a mechanism-based therapeutic approach that may improve both the efficacy and safety of insomnia treatment. Full article

Underweight in pregnant women adversely affects the next generation. Although young female underweight has become an important issue even in developed countries, the precise mechanisms that induce an underweight status in young women remains unknown. To examine the influence of feeding timing in young women on the following underweight conditions, we examined the effects of chronic light–dark cycle-reversed feeding restriction on post-restriction dietary behaviors using adult and young adult female rats. Eight- and 24-week-aged female Wistar rats were classified into three groups: (1) the control group (without time or calorie restriction), (2) the night-time-fed group that was fed only during the active phase, and (3) the daytime-fed group that was fed only during the non-active phase. After a 4-week feeding restriction, all groups were additionally fed ad libitum for 7 weeks with daily food intake and weight gain measurements. After sacrifice, mRNA expressions of neuropeptide Y (NPY), agouti-related protein (AgRP), orexin-A, pro-opiomelanocortin (POMC), and thyrotropin-releasing hormone (TRH) in the hypothalamus and leptin in the fatty tissues were examined by real-time PCR. Daytime-fed groups decreased food intake during restriction. After stress relief, adult rats showed a rebound increase in food intake beyond the level of the control group, whereas young adult rats showed no significant rebound response. At the end of the non-restricted period, both adult and young adult rats in the daytime-fed group reduced NPY expression in the hypothalamus. These findings indicate that recovery responses in food intake against chronic light–dark cycle-reversed stress are different between adult and young adult rats. The lower response in young adult rats may provide clues to elucidating a new mechanism for underweight status in young females. Full article

The comorbidity of obesity and anxiety represents a complex condition with substantial health implications, exacerbating metabolic burden while compromising psychological well-being. Neurons in the lateral hypothalamus (LH) synthesize orexin-A and orexin-B, neuropeptides that orchestrate feeding behavior and energy expenditure, thereby directly regulating energy homeostasis and associated behaviors. Functioning as integrative modulators, orexins coordinate autonomic, neuroendocrine, arousal, reward, and stress circuits. Dysregulation of orexin signaling is strongly implicated in metabolic disorders, particularly obesity, as well as in psychiatric conditions including anxiety and depression, highlighting its central role in their comorbidity. This review provides a comprehensive overview of recent advances in understanding orexin-A neural circuits in feeding regulation, emphasizing mechanistic insights into the interplay between orexin signaling, energy balance, and anxiety–obesity comorbidity. Furthermore, it critically evaluates sources of heterogeneous therapeutic outcomes and outlines future strategies for precise modulation of the orexin system to restore metabolic and emotional homeostasis. Full article

Background/Objectives: Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components of Semen Ziziphi Spinosae that exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the A_2AR remains to be elucidated. Methods: In the study, the involvement of A_2ARs in spinosin’s hypnotic effect was investigated using caffeine and further elucidated in A_2AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the A_2AR. Results: The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with A_2AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in A_2AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in A_2AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the A_2AR. MD simulations further demonstrated that spinosin had strong binding stability with the A_2AR. Conclusions: Our findings strongly suggest that spinosin exerts the hypnotic effects through the A_2AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin’s direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development. Full article

Growth hormone-releasing hormone receptor 1a (GHS-R1a) is a key G protein-coupled receptor (GPCR) governing feeding and energy homeostasis. Accumulating evidence shows that GHS-R1a forms functional heterodimers with multiple metabolic-related GPCRs, including dopamine 2 receptor (D2R), melanocortin 3 receptor (MC3R), 5-hydroxytryptamine 2c receptor (5-HT2cR), orexin receptor 1 (OX1R) and cannabinoid receptor 1 (CB1R). These heterodimers undergo distinct signal transduction reprogramming, generating novel physiological effects that are not observed with individual receptors: for instance, GHS-R1a/D2R mediates an atypical calcium signaling pathway to regulate appetite, while GHS-R1a/5-HT2cR antagonizes ghrelin-induced orexigenic effects. Meanwhile, diverse detection techniques, including co-immunoprecipitation and fluorescence resonance energy transfer, have been developed to identify and validate GHS-R1a heterodimerization, laying a solid foundation for mechanistic research. This review systematically summarizes the molecular mechanisms of GHS-R1a heterodimer formation, the characteristic signal regulation patterns of different heterodimers, and their specific regulatory roles in feeding circuits. Furthermore, we discuss the existing research gaps in this field, such as the lack of in vivo detection methods for heterodimers and the unclear structural basis of dimerization. Finally, we highlight the potential of targeting specific GHS-R1a heterodimers as a novel therapeutic strategy for obesity and anorexia, providing new directions for future pharmaceutical development and clinical translation. Full article

Cryptorchidism is one of the most frequently diagnosed developmental disorders of the male canine reproductive system, defined as the failure of one or both testes to descend into the scrotum. Physiologically, testicular descent is typically completed by six to eight weeks of age, although some authors extend this period to sixteen weeks. Failure of testicular descent beyond this timeframe is considered pathological. The condition has multiple causes and affects between 1% and 10% of the canine population. Genetics is the most significant factor, indicating the hereditary basis of cryptorchidism. In addition, increasing attention has been directed toward the potential impact of environmental and epigenetic factors on the incidence of cryptorchidism, suggesting that the condition may result from complex interactions between genetic predisposition and external influences. The effect of hormones (such as INSL3 and testosterone), mechanical factors (including narrowing of the inguinal canal, abnormalities of the gubernaculum, and shortening of the spermatic cord), and environmental factors (for example, exposure to external estrogens and maternal stress during pregnancy) all contribute to the development of this disorder. Recent results have emphasized the role of the orexin system, particularly the OX2R receptor, in regulating endocrine and reproductive functions in cryptorchid testes. Computed tomography is increasingly utilized in complex cases due to its high precision in localizing retained testes. Clinically, cryptorchidism may present unilaterally or bilaterally. Unilateral cryptorchidism may preserve partial fertility, whereas bilateral cryptorchidism results in complete infertility. Undescended testes may be located in the abdominal cavity or inguinal canal. Major complications include an increased risk of testicular cancer (Sertoli cell tumors and seminomas) and endocrine disorders leading to feminization. Diagnosis is based on clinical examination and imaging modalities such as ultrasound. Orchiectomy, involving the removal of both the retained and normally descended testicles, is thought to be the gold standard for treatment. This method helps avoid complications and the transmission of the defect to offspring. According to Fédération Cynologique Internationale (FCI) standards, affected individuals should not be used for breeding or shows. Early detection, surgical intervention, and consistent exclusion from breeding programs are the primary strategies for reducing the incidence of this disorder in the canine population. Full article

Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake stability, metabolic processes, and motivated behaviour—in the pathophysiology and treatment response of psychotic disorders. We aimed to investigate the relationships between the orexinergic system and psychoses. Methods: On 3 March 2026, we searched the PubMed, Scopus, PsycInfo/Articles and Cinahl databases for studies dealing with the orexin system and psychotic disorders and treatment response. Results: We found 20 eligible studies reporting variable and inconsistent alterations in orexin signalling in patients with schizophrenia. Studies were mostly cross-sectional and heterogeneous in design. Antipsychotic medications interfere with orexin-dependent pathways, potentially contributing to both therapeutic effects and adverse outcomes such as sleep disruption and metabolic dysregulation. Conclusions: While evidence from preclinical studies could point to an influence of dopaminergic activity through orexinergic mechanisms, with possible attenuation of antipsychotic-induced motor side effects and improvement of attentional deficits associated with NMDA receptor hypofunction, the utility of dual orexin receptor antagonists (DORAs) in psychoses is unclear. Despite the high prevalence of insomnia in schizophrenia, its pharmacological management remains suboptimal, with current treatments often limited by reduced efficacy or tolerability concerns. DORAs, which are currently approved medications for the treatment of insomnia, represent a novel and mechanistically distinct therapeutic option that may improve sleep while modulating arousal- and cognition-related circuits relevant to psychosis. Full article

In Italy, the breeding of alpacas (Vicugna pacos) is on the rise, driven by the value of their precious wool and their docile temperament. This growth is, however, severely limited by the species’ reproductive inefficiency. This study aimed to investigate the specific role of the neuropeptide orexin A (OxA) and its receptor OX1R in modulating testicular steroidogenesis in the alpaca, testing the hypothesis that the OxA/OX1R pathway stimulates testosterone production. Using testicular tissue from two groups of adult male alpacas (five- and seven-year-olds, n = 6 per group), we combined immunohistochemistry with ex vivo functional assays. Immunohistochemical analysis confirmed the expression of both OxA and OX1R in Leydig cells. Functional studies on testicular fragments demonstrated that OxA enhanced testosterone synthesis via OX1R activation. Furthermore, OxA reduced estradiol levels by suppressing aromatase activity and counteracted the inhibitory effect of Müllerian inhibiting substance (MIS) on testosterone secretion. These results provide the first evidence that the peripheral OX1R pathway is functionally involved in promoting a testosterone-dominant steroidogenic milieu in alpaca testes. This preliminary study identifies the orexin system as a potential target for developing strategies to improve reproductive management in this species. Full article

Background and Objectives: Intermittent fasting (IF) has emerged as a nutritional strategy capable of modulating circadian alignment, metabolic efficiency, and neuroendocrine regulation in individuals with obesity. Among the neurobiological mediators potentially involved, Orexin-A—a hypothalamic neuropeptide regulating arousal, appetite, and energy balance—may represent a key link between fasting patterns and metabolic homeostasis. This study aimed to evaluate the long-term metabolic and neuroendocrine effects of two intermittent fasting protocols, time-restricted feeding (16:8) and alternate-day fasting (5:2), compared with a hypocaloric Mediterranean diet used as a reference condition. Materials and Methods: Thirty adults with obesity (aged 20–40 years) were allocated to one of three dietary interventions—low-calorie Mediterranean diet, IF 16:8, or IF 5:2—based on habitual dietary patterns and followed prospectively for 12 months. Anthropometric parameters, metabolic indices, inflammatory markers (CRP, TNF-α, IL-6, IL-10), and circulating Orexin-A concentrations were assessed at baseline and at three-month intervals (T0–T3). Results: Both intermittent fasting protocols induced more rapid improvements in body mass index, adiposity, lipid profile, fasting glucose, and inflammatory markers compared with the Mediterranean diet. Among the IF strategies, the 16:8 regimen showed the most consistent and physiologically coherent pattern of adaptation, characterized by a progressive and sustained increase in Orexin-A levels. This response was strongly associated with enhanced metabolic flexibility, reduced systemic inflammation, and improved energy regulation over time. In contrast, the 5:2 protocol produced more variable metabolic and neuroendocrine responses, likely due to alternating cycles of marked caloric restriction and compensatory intake. Conclusions: Intermittent fasting, particularly the 16:8 time-restricted feeding protocol, appears to be an effective and sustainable chrononutritional strategy for obesity management. By reinforcing circadian organization, improving inflammatory balance, and activating orexinergic pathways, the 16:8 model emerges as a promising intervention to address key metabolic and neuroendocrine dysfunctions associated with obesity. Full article

Background: Malnutrition and sleep disturbances are common in childhood and are associated with neuropeptides that regulate appetite and circadian rhythms. Hypothalamic peptides such as orexin A, agouti-related protein (AgRP), proopiomelanocortin (POMC), and peptide YY (PYY) play important roles in energy balance and eating behavior; however, their specific functions in pediatric malnutrition remain unclear. This study aimed to determine the levels of these peptides in malnourished children and to examine their relationship with eating and sleep behaviors. Methods: This case–control, cross-sectional study included 99 children aged 5–15 years diagnosed with malnutrition and 85 age-matched healthy controls. Blood samples were collected from all participants, and peptide levels were measured using ELISA. Additionally, the Children’s Eating Behaviour Questionnaire (CEBQ) and the Children’s Sleep Habits Questionnaire (CSHQ) were administered to assess eating patterns and sleep behaviors. Statistical comparisons and hierarchical logistic regression analyses were performed. Results: Orexin A and PYY levels were significantly higher in malnourished children than in controls (p < 0.001). No significant group differences were found for AgRP and POMC, although AgRP tended to be lower and POMC higher in the malnutrition group. Regression analyses identified orexin A and PYY as significant predictors of malnutrition. Orexin A showed a positive correlation with emotional undereating. Sleep habits did not differ significantly between groups. Conclusions: Elevated orexin A and PYY levels may function as potential neuropeptidergic biomarkers of malnutrition. Their association with emotional eating highlights the psychobiological components of malnutrition. Further longitudinal studies are warranted to clarify causal mechanisms and support clinical translation. Full article

Background/Objectives: Intermittent fasting and ketogenic dietary approaches are increasingly investigated for their potential metabolic benefits in obesity. However, their long-term neuroendocrine effects—particularly those involving Orexin-A, a peptide implicated in energy regulation—remain poorly understood. The objective of this study was to compare the long-term metabolic, inflammatory, and orexinergic responses to different dietary strategies in adults with obesity. Methods: In this 12-month randomized, three-arm trial, 30 adults with obesity (BMI ≥ 30 kg/m²) were randomly assigned (1:1:1) to a hypocaloric ketogenic diet (KD), a 16:8 time-restricted eating regimen (TRF16:8), or a 5:2 intermittent fasting protocol (ADF5:2). Anthropometric parameters, body composition, fasting glucose, lipid profile, inflammatory cytokines (CRP, IL-6, TNF-α, IL-10), and plasma Orexin-A levels were assessed at baseline and every 3 months. Dietary adherence was monitored through structured logs and monthly assessments. Statistical analyses included repeated-measures models with sensitivity analyses adjusted for age and sex. Results: All participants completed the intervention. The ketogenic diet produced the largest sustained reductions in BMI, fat mass, fasting glucose, and total cholesterol over 12 months. TRF16:8 elicited more rapid early metabolic improvements and showed the most consistent longitudinal increase in Orexin-A levels. The ADF5:2 protocol resulted in moderate improvements across outcomes. In all groups, increases in Orexin-A were associated with markers of improved metabolic flexibility and reduced inflammation; however, mediation analyses were exploratory and non-causal. Between-group differences remained significant for fat mass, glucose, and Orexin-A trajectories after correction for multiple comparisons. Conclusions: The ketogenic diet was associated with the most pronounced long-term metabolic improvements, whereas 16:8 time-restricted eating yielded faster early responses and the most stable enhancement in Orexin-A levels. These findings indicate distinct metabolic and neuroendocrine adaptation profiles across dietary strategies. Given the small sample size, results should be interpreted cautiously, and larger trials are warranted to clarify the role of Orexin-A as a potential biomarker of dietary response in obesity. Full article

Global warming and the increasing frequency of marine heatwaves (MHWs) threaten marine ecosystems and aquaculture. For the economically important spotted seabass (L. maculatus), the neuroendocrine basis of its stage-specific thermal responses has yet to be elucidated. This study examined the transcriptomic, physiological, and behavioral adaptations to chronic heat stress in late larval and late juvenile seabass over 14 days. After thermal acclimation, larvae demonstrated a marked behavioral shift, preferring warmer waters (26–34 °C). While heat stress upregulated key thermosensory genes (e.g., trpv1, trpv4) in the brain across both stages, it induced distinct expression profiles in the skin, suggesting a developmental transition from peripheral to central dominance in thermosensation. Brain transcriptomics revealed stage-specific pathway activation: juveniles engaged in neuroactive ligand-receptor interactions and MAPK signaling, whereas larvae showed enrichment in phosphatidylinositol signaling and protein processing. Both stages showed activation of the hypothalamic-pituitary-interrenal (HPI) axis (upregulation of crh, crhr1, crhr2, pomc) and heat shock response (hsp70, hsp90), accompanied by elevated serum cortisol. Notably, energy metabolism diverged significantly: larvae maintained appetite and developed hyperglycemia, while juveniles exhibited severe feeding suppression and hypoglycemia, which was correlated with differential regulation of appetite genes (npy, orexin, cck). Our results elucidate the distinct neuroendocrine mechanisms underlying thermal acclimation in L. maculatus and provide a scientific basis for developing climate-resilient aquaculture practices for this species. Full article

Background/Objectives: Gestational exposure to a high-fat diet (HFD) reprograms hypothalamic orexigenic circuits prenatally. However, whether astrocytes, critical modulators of this system, are also imprinted by HFD in the fetal brain remains unknown. We investigated the impact of HFD on the prenatal neuroglial architecture of the lateral hypothalamic area (LHA). Methods: Female Wistar rats were fed a control or a 60% fat diet for 12 weeks. Upon reaching obesity (Lee index ≥ 310), dams were mated. Fetuses were harvested via cesarean section at term, and their brains were processed for immunohistochemistry and morphometry to assess cell proliferation, orexin neuron density, and astrocytic reactivity in the LHA. Results: HFD significantly increased cell proliferation and orexinergic neuron density, and induced early signs of astrocyte reactivity in the fetal LHA. These findings reveal that both neuronal and glial components of the LHA orexigenic axis are structurally reprogrammed before birth. Conclusions: This study provides the first evidence that HFD simultaneously alters neuronal and glial developmental trajectories in the fetal hypothalamus. The concurrent programming of astrocytes and orexigenic neurons suggests a prenatal origin for neuroinflammatory susceptibility, reframing obesity as a neurodevelopmental disorder shaped by early life nutritional environments. Full article