Kahyee Hor, Laura Dearden, Emily Herzstein, Susan Ozanne, Giles Hardingham, Amanda J. Drake
{"title":"Maternal high fat and high sugar diet impacts on key DNA methylation enzymes in offspring brain in a sex-specific manner","authors":"Kahyee Hor, Laura Dearden, Emily Herzstein, Susan Ozanne, Giles Hardingham, Amanda J. Drake","doi":"10.1111/jne.70046","DOIUrl":"10.1111/jne.70046","url":null,"abstract":"<p>Maternal obesity associates with an increased risk of offspring neurodevelopmental disorders. Although the underlying mechanism(s) remain unclear, evidence suggests a role for altered DNA methylation. We utilized a murine model of diet-induced obesity to investigate the impact of maternal obesity on the offspring brain transcriptome and DNA methylation. C57Bl/6 dams were fed high-fat high-sugar (HFD, <i>n</i> = 7) or control (CON, <i>n</i> = 7) diets. Maternal obesity/hyperglycemia associated with offspring growth restriction, with brain-sparing specifically in females. Postnatal hypoglycemia was seen in HFD males, but not females. The 3′ RNA-sequencing revealed perturbations in metabolic and cell differentiation pathways in neonatal male and female offspring frontal cortex and cerebellum. Compared with controls, HFD males, but not females, had lower cortical and cerebellar DNMT gene and protein expression, and reduced cerebellar TET enzyme mRNA. Whilst female offspring had lower cerebellar 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) than males, there were no effects of HFD on 5mC/5hmC in cortex or cerebellum in either sex. Our data suggest that maternal obesity has sex-specific effects on fetal neurodevelopment, including enzymes involved in DNA methylation/demethylation. These mechanisms may play a role in the increased risk of neurodevelopmental disorders following obese/diabetic pregnancies, including increased male susceptibility to these disorders.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ammir Y. Helou, Camila de Carvalho, Larissa A. do Carmo, Jackson C. Bittencourt
{"title":"Litter sex composition influences plasma prolactin levels but not the melanin-concentrating hormone immunoreactive neurons in the medial preoptic area of late lactating Long-Evans rats","authors":"Ammir Y. Helou, Camila de Carvalho, Larissa A. do Carmo, Jackson C. Bittencourt","doi":"10.1111/jne.70043","DOIUrl":"10.1111/jne.70043","url":null,"abstract":"<p>This study examines the influence of litter sex composition on melanin-concentrating hormone immunoreactive (MCH-ir) neurons in the ventromedial medial preoptic area (vmMPOA) and on plasma prolactin levels in lactating rats. MCH is a critical regulator of maternal behavior and displays sexual dimorphism within the MPOA, making it an important target for understanding neuroendocrine adaptations in lactation. Prolactin, a pivotal hormone in lactation and maternal care, was also assessed to elucidate its interaction with litter sex composition. Thirty lactating female rats were divided into five experimental groups based on litter sex composition: all-male (10 male pups), all-female (10 female pups), balanced control (five male and five female pups), predominantly male (seven male and three female pups), and predominantly female (three male and seven female pups). On post-partum day 19 (PPD19), the dams were euthanized for biological analysis. Blood samples were collected for plasma prolactin quantification, and the brains were processed to analyze MCH-ir neurons in the vmMPOA. Results showed no significant differences in food and water intake or the number of MCH-ir neurons in the vmMPOA among experimental groups. However, significant variation in prolactin levels was observed, with the all-male offspring group exhibiting the highest levels (mean prolactin level 23.9 ng/mL, <i>p</i> < .001), followed by the all-female group (20.3 ng/mL, <i>p</i> < .01), compared to the control group (14.3 ng/mL). Additionally, the all-male group showed a reduction in body weight gain. These results suggest that although litter sex composition does not alter the number of MCH-ir neurons in the vmMPOA, it significantly impacts maternal prolactin levels. This differential prolactin regulation may reflect distinct physiological demands or caregiving behaviors imposed by homogeneous litters, which could, in turn, influence maternal energy balance, lactation efficiency, and adaptive maternal responses. Understanding these sex-specific influences on maternal neuroendocrine function has important implications for comprehending maternal care dynamics and energy allocation during lactation.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shumin Wang, Shuting Ren, Siting Lv, Yuankun Liu, Keke Xing, Ting Zhang, Xiaohang Jin, Juan Shi
{"title":"The Analgesic and Antidepressant Role of Oxytocin-Containing Neurons in the Hypothalamic Paraventricular Nucleus in Mice With Spared Nerve Injury","authors":"Shumin Wang, Shuting Ren, Siting Lv, Yuankun Liu, Keke Xing, Ting Zhang, Xiaohang Jin, Juan Shi","doi":"10.1111/jne.70045","DOIUrl":"10.1111/jne.70045","url":null,"abstract":"<p>Neuropathic pain is the debilitating chronic pain frequently comorbid with anxiety and depression. The mechanism and treatment strategy of neuropathic pain are to be elucidated. Oxytocin (OXT)-containing neurons (simplified as OXT neurons) in the hypothalamic paraventricular nucleus (PVN) have been highlighted recently in the field of pain regulation and social function. But so far, the adaptive change and endogenous function of the neurons in neuropathic pain remain unclear. By immunofluorescent staining, we investigated the changes in FOSB expression in OXT neurons in the PVN with the development of neuropathic pain induced by spared nerve injury (SNI). The effect of neuronal activation on pain, as well as comorbid anxiety and depression, was subsequently assessed by chemogenetic manipulation. FOSB expression in the OXT neurons was significantly increased at 1 day and then gradually decreased at 7, 28, and 49 days after SNI. Activation of OXT neurons in the PVN by the OXT promoter-directed hM3Dq virus or by the Cre-loxP system in OXT-Cre mice significantly improved the mechanical pain, cold pain, and depressive-like behaviors in male and female mice, but exerted weak anxiolytic effects in female mice. These results demonstrate the altered activational status and the analgesic/antidepressant role of the OXT neurons in the PVN, thus providing a cellular-based strategy for the comprehensive treatment of neuropathic pain.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vanlal Rempuia, Guruswami Gurusubramanian, Vikas Kumar Roy
{"title":"Exogenous visfatin suppresses pituitary gonadotrophins and stimulates testosterone secretion in a male mouse","authors":"Vanlal Rempuia, Guruswami Gurusubramanian, Vikas Kumar Roy","doi":"10.1111/jne.70044","DOIUrl":"10.1111/jne.70044","url":null,"abstract":"<p>Visfatin expression has been shown in the testis and pituitary. However, the role of visfatin in the pituitary and testis axis is fragmentary. Furthermore, no study has shown the effects of visfatin on the pituitary gonadotrophins and testicular steroid hormonal secretions in a male mouse. The present study has investigated the effects of exogenous visfatin (most likely a state of hypervisfatinemia) on the gonadotrophins, testosterone, estradiol, androstenedione, and progesterone in a male mouse. The exogenous visfatin was given for 35 days, which covers one spermatogenic cycle. The circulating testosterone was elevated after visfatin treatment, along with down-regulation of AR and steroidogenic markers in the testis. However, the expression of CYP17 was up-regulated in visfatin-treated testis. Visfatin treatment also elevated apoptosis in the different germ cells of the testis. The levels of circulating LH and FSH were also suppressed after visfatin treatment. The immunolocalization of AR exhibited decreased abundance in the pituitary of visfatin-treated mice; thus, it can be suggested that pituitary gonadotrophins secretion might be suppressed by direct action of visfatin rather than via elevated testosterone. In conclusion, our results showed that exogenous visfatin suppresses gonadotrophins and stimulates testicular testosterone secretions in a differential manner. Visfatin has inhibitory effects on pituitary gonadotrophins secretion and stimulatory effects on testosterone secretion from the testis. Thus, conditions similar to hypervisfatinemia likely impair the release of hormones from the pituitary and testis.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katharina Karges, Marina Kunstreich, Ulrich-Frank Pape, Jörg Fuchs, Christian Vokuhl, Michael Abele, Dominik T. Schneider, Ines B. Brecht, Constantin Lapa, Michael C. Frühwald, Peter Vorwerk, Antje Redlich, Michaela Kuhlen
{"title":"Pancreatic neuroendocrine tumors in children and adolescents—Data from the German MET studies (1997–2023)","authors":"Katharina Karges, Marina Kunstreich, Ulrich-Frank Pape, Jörg Fuchs, Christian Vokuhl, Michael Abele, Dominik T. Schneider, Ines B. Brecht, Constantin Lapa, Michael C. Frühwald, Peter Vorwerk, Antje Redlich, Michaela Kuhlen","doi":"10.1111/jne.70039","DOIUrl":"10.1111/jne.70039","url":null,"abstract":"<p>Pancreatic neuroendocrine tumors (panNETs) are rare pediatric malignancies with age-specific clinical and biological features. Data on their presentation, management, and outcomes remain limited. This retrospective study analyzed 28 pediatric panNET cases from the German Malignant Endocrine Tumor (MET) Registry enrolled between 1997 and 2024. Clinical presentation, diagnostics, and treatment were evaluated to identify prognostic factors and outcomes. The cohort included 18 females (64.3%) and 10 males (35.7%), with a median age at diagnosis of 14.7 years. Nonfunctional tumors predominated (75%). Genetic syndromes were identified in 17.9% of patients. Localized disease showed a 3-year overall survival (OS) of 100%, while metastatic disease had a 3-year OS of 50.9%. Event-free survival was significantly associated with the presence of distant metastases (M0 vs. M1, <i>p</i> = .0082) and complete surgical resection (R<sub>0</sub> vs. R<sub>1/2</sub> vs. no resection, <i>p</i> = .0077) but not with lymph node involvement (N0 vs. N1, <i>p</i> = .12), tumor localization within the pancreas (head vs. body vs. tail, <i>p</i> = .86), the extent of the primary tumor (pT1-2 vs. pT3-4, <i>p</i> = 1.0), pathological grade (G1 vs. G2-3, <i>p</i> = .28), or proliferation index (Ki67 ≤ 10% vs. >10%, <i>p</i> = .11). This study underscores the importance of disease stage and surgical resection as key prognostic factors in pediatric panNETs. It highlights the need for pediatric-specific management guidelines, integration of genetic screening, and expanded molecular profiling to optimize outcomes for children and adolescents with panNETs.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kazhan Mollazadegan, Johan Botling, Britt Skogseid, Barbro Eriksson, Lovisa Falkman, Liang Zhang, Ieva Lase, Staffan Welin, Anders Sundin, Joakim Crona
{"title":"The impact of re-characterizing metastatic pancreatic neuroendocrine tumors: A prospective study","authors":"Kazhan Mollazadegan, Johan Botling, Britt Skogseid, Barbro Eriksson, Lovisa Falkman, Liang Zhang, Ieva Lase, Staffan Welin, Anders Sundin, Joakim Crona","doi":"10.1111/jne.70040","DOIUrl":"10.1111/jne.70040","url":null,"abstract":"<p>The biology of metastatic pancreatic neuroendocrine tumors (panNET) may alter over time. It remains to be defined if, how, and when this patient group should be recommended to re-evaluate the characteristics of their disease. This prospective single-center, longitudinal cohort study at Uppsala University Hospital, Sweden (NCT03130205), included metastatic panNET patients with progressive disease to participate in a standardized re-characterization protocol: clinical and biochemical analyses, core-needle biopsy, and dual-positron emission tomography/computed tomography (PET/CT) (<sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) and Gallium-68 DOTATOC (<sup>68</sup>Ga-DOTATOC)) with NETPET score assessments. At further disease progression, a second re-characterization was offered. The proportion of patients with a clinically significant change is reported and defined as information that could lead to a change in the therapeutic algorithm proposed in the European Neuroendocrine Tumor Society (ENETS) guidelines. Between 2017 and 2021, 21 patients with progressive metastatic panNETs were included. Before inclusion, 19 tumors were grade (G) 1 or 2, and two were G3. Sixteen patients underwent biopsy with collection of adequate tumor material, of whom 81.3% (<i>n</i> = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (<i>n</i> = 8/16). Twelve and 15 patients were positive on <sup>18</sup>F-FDG- and <sup>68</sup>Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (<i>n</i> = 2), P2b (<i>n</i> = 12), and P3b (<i>n</i> = 1). A clinically significant change was noted among 62% (<i>n</i> = 13/21) of patients at first re-characterization, leading to therapy change in 7 positron emission tomography/computed tomography (PET/CT) patients. After the second re-characterization, a significant clinical change occurred in 43% (<i>n</i> = 3/7) with a shift in therapy for one patient. This study shows that a considerable number of progressive metastatic panNETs experience significant changes in their disease characteristics over time. This may result in a revised treatment plan and highlights the need to re-evaluate all relevant aspects of panNET disease. Such comprehensive re-characterization is particularly crucial in the context of clinical trial inclusion.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas J. Degroat, Sarah E. Paladino, Benjamin A. Samuels, Troy A. Roepke
{"title":"Chronic variable mild stress alters the transcriptome and signaling properties of the anterodorsal bed nucleus of the stria terminalis in a sex-dependent manner","authors":"Thomas J. Degroat, Sarah E. Paladino, Benjamin A. Samuels, Troy A. Roepke","doi":"10.1111/jne.70041","DOIUrl":"10.1111/jne.70041","url":null,"abstract":"<p>Chronic stress is a physiological state marked by dysregulation of the hypothalamic–pituitary–adrenal axis and high circulating levels of stress hormones, such as corticosterone in mice or cortisol in humans. This dysregulated state may result in the development of mood disorders, but the process by which this occurs is still unknown. The bed nucleus of the stria terminalis (BNST) serves as an integration center for stress signaling and is therefore likely an important area for the development of mood disorders. This project utilized a chronic variable mild stress (CVMS) paradigm to persistently stress mice for 6 weeks, followed by RNA-Sequencing of the anterodorsal (ad) BNST and electrophysiology of corticotropin-releasing hormone-expressing cells in the adBNST. Our results show significant sex biases in the transcriptome of the adBNST as well as effects of CVMS on the transcriptome of the adBNST specifically in males. Female-biased genes are related to synaptic transmission, while male-biased genes are related to RNA processing. Stress-sensitive genes in males are related to synaptic transmission and synapse formation. Additionally, electrophysiology data showed that CVMS suppressed the M-current in males but not females. However, CVMS increased the strength of excitatory post-synaptic currents in females but not males. This suggests significant differences in how males and females process chronic stress. It also suggests that the BNST is more sensitive to chronic stress in males than in females.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hanna Gonzalez, Lei Cheng, Qing Chang, Paul E. Gold, Diego Perez-Tilve, YanYan Wang
{"title":"Overexpression of the short isoform of the dopamine D2 receptor causes diet-induced obesity and hyperglycemia in mice","authors":"Hanna Gonzalez, Lei Cheng, Qing Chang, Paul E. Gold, Diego Perez-Tilve, YanYan Wang","doi":"10.1111/jne.70042","DOIUrl":"10.1111/jne.70042","url":null,"abstract":"<p>Dopamine and dopamine D2R receptors (D2R) are involved in regulating eating behavior and endocrine and metabolic functions. D2R exists in two D2R isoforms: D2L (long form) and D2S (short form). Little is known if the changes in the expression levels of D2S and D2L would cause metabolic alterations. Here, we examined the role of these two D2R isoforms in obesity and glucose homeostasis. Mice of two genotypes were fed a higher fat diet (HFD). Body weight and food intake were monitored chronically, and various fat pads were dissected. Glucose tolerance and insulin tolerance tests were conducted. Energy expenditure and respiratory exchange ratio were measured via indirect calorimetry. We found when feeding with HFD, dopamine D2L knockout (D2L KO) mice (expressing purely D2S) of both female and male gained significantly more body weight than wild-type (WT) mice (expressing predominantly D2L) of both sexes. In addition, when feeding HFD, D2L KO mice showed an increased food intake compared to WT mice. Furthermore, when feeding HFD, both female and male D2L KO mice displayed impaired glucose tolerance. There were no significant differences in energy expenditure, respiratory quotient, and insulin sensitivity between D2L KO and WT mice. These results suggest that an increased expression level of D2S to D2L makes mice prone to obesity and hyperglycemia. Our findings identify a new risk factor contributing to the development of metabolic syndrome and increase our understanding of pathophysiological mechanisms leading to weight gain and diabetes.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}