Disturbance of testosterone cycle in favism-induced male rats is prevented by pracaxi oil oral administration.

OBJECTIVES: Favism is a metabolic disease while pracaxi oil is a strong antioxidant agent. This study evaluates anti-infertility activity and assists normal male fertilization of pracaxi oil in favism-induced male rats. METHODS: A 36 male albino rats of six equal sets were each with 6 rats; Control, Pracaxi oil (1 mL), and Pracaxi oil (2 mL), Favism-induced male rats-, Pracaxi oil (1 mL) + Favism-induced male rats, and Pracaxi oil (2 mL) + Favism-induced male rats groups. Blood parameters, liver function, serum male hormones were determined. Glucose-6-phosphate dehydrogenase, 3ß-hydroxysteroid dehydrogenase, total protein, and cholesterol in testis were estimated. Sodium/potassium-ATPase and antioxidants in the hypothalamus, testis, and sperm were assessed. Sperm count, motility, and abnormality, and sperm monoclonal proliferating antibody Ki-67 were evaluated. RESULTS: Favism decreased blood parameters, liver function, superoxide dismutase, glutathione, serum testosterone and dehydroepiandrosterone sulfate, sperm count and motility, sodium/potassium-ATPase activity while increased malondialdehyde, serum follicle stimulating hormone, sex hormone binding globulin, and luteinizing hormone, glucose-6-phosphatedehydrogenase, 3ß-hydroxysteroid dehydrogenase, cholesterol, total protein, sperm abnormality, the percentage of spermatogonia, 1st spermatocyte, 2nd spermatocyte, and spermatid in the testis. Furthermore, two doses of pracaxi oil to favism-induced male rats back all of aforementioned parameters to be close control values where a higher dose of pracaxi oil had an efficient impact than a lower dose. CONCLUSIONS: Pracaxi oil protects the hypothalamic-pituitary-gonad axis, and preserves sperm quality in favism-induced male rats.

Volumetric analysis of the hypothalamic subunits in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is associated with structural brain damage and cognitive impairment. The hypothalamus plays a crucial role in regulating sleep and wakefulness. We aimed to evaluate hypothalamic subunit volumes in patients with OSA. METHODS: We enrolled 30 participants (15 patients with OSA and 15 healthy controls (HC)). Patients with OSA underwent complete overnight polysomnography (PSG) examination. All the participants underwent MRI. The hypothalamic subunit volumes were calculated using a segmentation technique that trained a 3D convolutional neural network. RESULTS: Although hypothalamus subunit volumes were comparable between the HC and OSA groups (lowest p = .395), significant negative correlations were found in OSA patients between BMI and whole left hypothalamus volume (R = -0.654, p = .008), as well as between BMI and left posterior volume (R = -0.556, p = .032). Furthermore, significant positive correlations were found between ESS and right anterior inferior volume (R = 0.548, p = .042), minimum SpO2 and the whole left hypothalamus (R = 0.551, p = .033), left tubular inferior volumes (R = 0.596, p = .019), and between the percentage of REM stage and left anterior inferior volume (R = 0.584, p = .022). CONCLUSIONS: While there were no notable differences in the hypothalamic subunit volumes between the OSA and HC groups, several important correlations were identified in the OSA group. These relationships suggest that factors related to sleep apnea severity could affect hypothalamic structure in patients.

Differential activation of lateral parabrachial nuclei and their limbic projections during head compared with body pain: A 7-Tesla functional magnetic resonance imaging study.

Pain is a complex experience that involves sensory, emotional, and motivational components. It has been suggested that pain arising from the head and orofacial regions evokes stronger emotional responses than pain from the body. Indeed, recent work in rodents reports different patterns of activation in ascending pain pathways during noxious stimulation of the skin of the face when compared to noxious stimulation of the body. Such differences may dictate different activation patterns in higher brain regions, specifically in those areas processing the affective component of pain. We aimed to use ultra-high field functional magnetic resonance imaging (fMRI at 7-Tesla) to determine whether noxious thermal stimuli applied to the surface of the face and body evoke differential activation patterns within the ascending pain pathway in awake humans (n=16). Compared to the body, noxious heat stimulation to the face evoked more widespread signal changes in prefrontal cortical regions and numerous brainstem and subcortical limbic areas. Moreover, facial pain evoked significantly different signal changes in the lateral parabrachial nucleus, substantia nigra, paraventricular hypothalamus, and paraventricular thalamus, to those evoked by body pain. These results are consistent with recent preclinical findings of differential activation in the brainstem and subcortical limbic nuclei and associated cortices during cutaneous pain of the face when compared with the body. The findings suggest one potential mechanism by which facial pain could evoke a greater emotional impact than that evoked by body pain.

Androgens suppress corticosteroid binding globulin in male mice, affecting the endocrine stress response.

Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary adrenocorticotropic hormone (ACTH) levels. Stress-induced total plasma corticosterone levels were increased, while the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor (AR) knock-out animals, compared to wild-type litter mates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall our data demonstrate that, in mice, tonic AR activation affects CBG levels, in conjunction with effects on gene expression and HPA-axis reactivity.

Impact of sympathetic hyperactivity induced by brain microglial activation on organ damage in sepsis with chronic kidney disease.

BACKGROUND: Sympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD. METHODS AND RESULTS: In protocol 1, male Sprague-Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group. CONCLUSIONS: In septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN.

Transcriptomic changes in the hypothalamus of mice with chronic migraine: Activation of pathways associated with neuropathic inflammation and central sensitization.

Chronic migraine is a common central nervous system disorder characterized by recurrent, pulsating headaches. However, the extent and mechanisms of hypothalamic involvement in disease progression have not been thoroughly investigated. Herein, we created a chronic migraine mouse model using repeated intraperitoneal injections of nitroglycerin. We performed transcriptomic sequencing on the hypothalamus of mice with chronic migraine and control mice under normal physiological conditions, followed by differential gene set enrichment and functional analysis of the data. Additionally, we examined the intrinsic connection between chronic migraine and sleep disorders using transcriptomic sequencing data from sleep-deprived mice available in public databases. We identified 39 differentially expressed genes (DEGs) in the hypothalamus of a mouse model of chronic migraine. Functional analysis of DEGs revealed enrichment primarily in signaling transduction, immune-inflammatory responses, and the cellular microenvironment. A comparison of the transcriptomic data of sleep-deprived mice revealed two commonly expressed DEGs. Our findings indicate that the hypothalamic DEGs are primarily enriched in the PI3K/AKT/mTOR pathway and associated with the NF-κB/NLRP3/IL-1 ß pathway activation to maintain the central sensitization of the chronic migraine. Chronic migraine-induced gene expression changes in the hypothalamus may help better understand the underlying mechanisms and identify therapeutic targets.

Kynurenic Acid Modulates the Expression of Genes and the Activity of Cellular Antioxidant Enzymes in the Hypothalamus and Hippocampus in Sheep.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 µg/60 µL/30 min, KYNA20) and higher (4 × 25 µg/60 µL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

A single intravenous reelin injection restores corticosterone-induced neurochemical and behavioral alterations in dams during the post-partum period.

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD). Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 µg) or vehicle injection. Results: Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally. Discussion: This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose-response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.

Monosome Stalls the Translation Process Mediated by IGF2BP in Arcuate Nucleus for Puberty Onset Delay.

Puberty onset through hypothalamic-pituitary-gonad (HPG) axis as an important reproductive event in postnatal development is initiated from hypothalamic arcuate nucleus (ARC). The growing evidence indicates that translational control also plays an essential role in the final expression of gonadotropin genes. To investigate the role of protein translation and behavior of ribosomes in pubertal onset, the global profiles of transcriptome, single ribosome (monosome), polysome, and tandem mass tag proteome were comprehensively investigated in rat hypothalamic ARCs of different pubertal stages using RNA sequencing, polyribo sequencing, and mass spectrum. Transcriptome-wide enrichments of N6-methyladenosine and IGF2BP2 were investigated using meRIP and RIP sequencing. Monosome was robustly enriched on a large proportion of mRNA in early puberty rats (postnatal day (PND)-25) compared to late puberty (PND-35 and PND-45). Monosome-enriched mRNAs, including HPG axis-related genes, had a large number of upstream ORFs (uORF, < 100 nt) and displayed translational repression in early puberty. Furthermore, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) could particularly interact with and facilitate monosome to bind with mRNA in early puberty. Finally, ectopic over-expression of IGF2BP2 in hypothalamic ARC via lateral ventricle injection in vivo could recruit monosome to aggregate on mRNA and delay puberty onset. We uncovered a novel regulatory mechanism of IGF2BP2 and monosome for translational control in puberty onset, which shed light on the neuroendocrine regulatory network involved in HPG axis activation.

Exploring the Link between Premature Ovarian Insufficiency, Insomnia and Circadian Pathways.

OBJECTIVE: To establish an interaction network for genes related to premature ovarian insufficiency (POI) and insomnia, and to identify biological processes that connect POI to the physiological clock. METHODS: Previously reported lists of genes associated to POI and insomnia were contrasted and their intersection was used as input on protein-protein interaction analyses. POI-associated genes were contrasted with gene expression markers for neural circadian control and enriched pathways among their shared content were dissected. RESULTS: The functional network generated from the intersection between POI and insomnia gene lists pointed to the central nervous system as the most relevant cellular context for this connection. After identifying POI-associated genes that play a role in neural circadian patterns, we observed the disruption of pathways related to the hypothalamic-pituitary-gonadal axis as the major genetic link between ovarian function and circadian neural circuits. CONCLUSIONS: These findings highlight neurological mechanisms that support the POI-insomnia interplay.

Resveratrol: A Multifaceted Guardian against Anxiety and Stress Disorders-An Overview of Experimental Evidence.

The medicinal properties of resveratrol have garnered increasing attention from researchers. Extensive data have been accumulated on its use in treating cardiovascular diseases, immune system disorders, cancer, neurological diseases, and behavioral disorders. The protective mechanisms of resveratrol, particularly in anxiety-related stress disorders, have been well documented. However, less attention has been given to the side effects of resveratrol. This review explores not only the mechanisms underlying the anxiolytic effects of resveratrol but also the mechanisms that may lead to increased anxiety following resveratrol treatment. Understanding these mechanisms is crucial for enhancing the efficacy of resveratrol in managing anxiety disorders associated with stress and PTSD.

Curcumin nanoparticles in heat stroke management.

OBJECTIVE: The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. METHODS: Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. RESULTS: PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood-brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. CONCLUSION: By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. SIGNIFICANCE: This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.

Acetate attenuates hypothalamic pyroptosis in experimentally induced polycystic ovarian syndrome.

This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.

Transcriptome analysis reveals miRNA expression profiles in hypothalamus tissues during the sexual development of Jining grey goats.

BACKGROUND: Exploring the physiological and molecular mechanisms underlying goat sexual maturation can enhance breeding practices and optimize reproductive efficiency and is therefore substantially important for practical breeding purposes. As an essential neuroendocrine organ in animals, the hypothalamus is involved in sexual development and other reproductive processes in female animals. Although microRNAs (miRNAs) have been identified as significant regulators of goat reproduction, there is a lack of research on the molecular regulatory mechanisms of hypothalamic miRNAs that are involved in the sexual development of goats. Therefore, we examined the dynamic changes in serum hormone profiles and hypothalamic miRNA expression profiles at four developmental stages (1 day (neonatal, D1, n = 5), 2 months (prepubertal, M2, n = 5), 4 months (sexual maturity, M4, n = 5), and 6 months (breeding period, M6, n = 5)) during sexual development in Jining grey goats. RESULTS: Transcriptome analysis revealed 95 differentially expressed miRNAs (DEMs) in the hypothalamus of goats across the four developmental stages. The target genes of these miRNAs were significantly enriched in the GnRH signalling pathway, the PI3K-Akt signalling pathway, and the Ras signalling pathway (P < 0.05). Additionally, 16 DEMs are common among the M2 vs. D1, M4 vs. D1, and M6 vs. D1 comparisons, indicating that the transition from D1 to M2 represents a potentially critical period for sexual development in Jining grey goats. The bioinformatics analysis results indicate that miR-193a/miR-193b-3p-Annexin A7 (ANXA7), miR-324-5p-Adhesion G protein-coupled receptor A1 (ADGRA1), miR-324-3p-Erbb2 receptor tyrosine kinase 2 (ERBB2), and miR-324-3p-Rap guanine nucleotide exchange factor 3 (RAPGEF3) are potentially involved in biological processes such as hormone secretion, energy metabolism, and signal transduction. In addition, we further confirmed that miR-324-3p targets the regulatory gene RAPGEF3. CONCLUSION: These results further enrich the expression profile of hypothalamic miRNAs in goats and provide important insights for studying the regulatory effects of hypothalamic miRNAs on the sexual development of goats after birth.

Integrated Microbiome and Metabolome Analysis Reveals Hypothalamic-Comorbidities Related Signatures in Craniopharyngioma.

Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP-associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP-enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP-depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up-regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi-omics analysis in the Rax-CreERT2::BrafV600E/+::PtenFlox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co-variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up-regulated purine metabolism as signatures of CP-associated hypothalamic-comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP-associated hypothalamic-comorbidities.

Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer's disease.

BACKGROUND: Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD. RESULTS: Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid ß (Aß) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aß load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model. CONCLUSION: Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

The Impact of the Endocrine and Immunological Function of Adipose Tissue on Reproduction in Women with Obesity.

Obesity, which leads to metabolic dysregulation and body function impairment, emerges as one of the pressing health challenges worldwide. Excessive body fat deposits comprise a dynamic and biologically active organ possessing its own endocrine function. One of the mechanisms underlying the pathophysiology of obesity is low-grade systemic inflammation mediated by pro-inflammatory factors such as free fatty acids, lipopolysaccharides, adipokines (including leptin, resistin and visfatin) and cytokines (TNF-α, IL-1ß, Il-6), which are secreted by adipose tissue. Together with obesity-induced insulin resistance and hyperandrogenism, the exacerbated immune response has a negative impact on the hypothalamic-pituitary-gonadal axis at all levels and directly affects reproduction. In women, it results in disrupted ovarian function, irregular menstrual cycles and anovulation, contributing to infertility. This review focuses on the abnormal intracellular communication, altered gene expression and signaling pathways activated in obesity, underscoring its multifactorial character and consequences at a molecular level. Extensive presentation of the complex interplay between adipokines, cytokines, immune cells and neurons may serve as a foundation for future studies in search of potential sites for more targeted treatment of reproductive disorders related to obesity.

Consensus guidelines for the management of craniopharyngioma in low- and middle-income countries.

Craniopharyngiomas are benign, extra-axial epithelial tumours originating from the pituitary stalk, impacting areas such as the hypothalamus, optic chiasm, and various cranial nerves. These tumours present unique surgical challenges due to their proximity to critical neurovascular structures. Management typically involves maximal safe resection as the primary approach. However, in low- and middle-income countries (LMICs), factors like late presentation, higher risks of endocrine and visual complications, frequent recurrence, and potential for incomplete resection complicate treatment. These challenges are exacerbated by limited access to specialised expertise and surgical equipment, increasing the risk of damage during surgery compared to High- Income Countries. This manuscript outlines management guidelines tailored for LMICs, emphasizing that a combination of surgical resection and chemoradiation therapy, as advised by a neuro-oncology tumour board, often yields the best outcomes.

Morning resting hypothalamus-dorsal striatum connectivity predicts individual differences in diurnal sleepiness accumulation.

While the significance of obtaining restful sleep at night and maintaining daytime alertness is well recognized for human performance and overall well-being, substantial variations exist in the development of sleepiness during diurnal waking periods. Despite the established roles of the hypothalamus and striatum in sleep-wake regulation, the specific contributions of this neural circuit in regulating individual sleep homeostasis remain elusive. This study utilized resting-state functional magnetic resonance imaging (fMRI) and mathematical modeling to investigate the role of hypothalamus-striatum connectivity in subjective sleepiness variation in a cohort of 71 healthy adults under strictly controlled in-laboratory conditions. Mathematical modeling results revealed remarkable individual differences in subjective sleepiness accumulation patterns measured by the Karolinska Sleepiness Scale (KSS). Brain imaging data demonstrated that morning hypothalamic connectivity to the dorsal striatum significantly predicts the individual accumulation of subjective sleepiness from morning to evening, while no such correlation was observed for the hypothalamus-ventral striatum connectivity. These findings underscore the distinct roles of hypothalamic connectivity to the dorsal and ventral striatum in individual sleep homeostasis, suggesting that hypothalamus-dorsal striatum circuit may be a promising target for interventions mitigating excessive sleepiness and promoting alertness.

Principal components analysis on genes related to inflammasome complex and microglial activation in the hypothalamus of obese mice treated with semaglutide (GLP-1 analog).

We studied the effect of semaglutide (glucagon-like peptide type 1 agonist) on hypothalamic pro-inflammatory genes in diet-induced obese mice. Male C57BL/6J mice were fed a control (C) or high-fat (HF) diet for 16 weeks, then divided into six groups and maintained for an additional four-week study: C, C+semaglutide (CS), C pair-feeding (CP), HF, HF+semaglutide (HFS), and HF pair-feeding (HFP).Weight gain (WG), food efficiency (FE), and plasmatic biochemistry were determined. The hypothalamus was removed and prepared for molecular analysis. Semaglutide reduced WG and FE in the HF group. High cytokines levels (tumor necrosis factor alpha, TNF alpha, monocyte chemoattractant protein 1, MCP1, and Resistin) in HF mice were reduced in HFS mice. High pro-inflammatory gene expressions were seen in HF (toll-like receptor 4, Tlr4; Mcp1; interleukin 6, Il6; Tnfa), inflammasome complex (Pirina domain-containing receptor 3, Nlrp3; Caspase 1, Il1b, Il18), and microglial activation (ionized calcium-binding adapter molecule 1, Iba1; cluster differentiation 68, Cd68; argirase 1, Arg1) but mitigated in HFS. The principal components analysis (PCA) based on these markers in a PC1 x PC2 scatterplot put HF and HFP together but far away from a cluster formed by C and HFS, indicating little significance of weight loss (HFP) but decisive action of semaglutide (HFS) in the results. In conclusion, semaglutide benefits hypothalamic pro-inflammatory genes, inflammasome complex, and microglial activation independent of the weight loss effect. Since GLP-1 receptor agonists such as semaglutide are already indicated to treat obesity and diabetes, the potential translational effects on neuroinflammation should be considered.