Journal Of Neuroendocrinology[JOURNAL]
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200 papers
Fragility fractures in well-differentiated gastroenteropancreatic neuroendocrine tumors: Results from a multicentered retrospective study.
Brunetti A, Cellini M, Lavezzi E … +13 more , Zerbi A, Ferrillo G, Birtolo MF, Berruti A, Cavati G, Lagana M, Gennari L, Girometti R, Zuiani C, Grimaldi F, Lania AG, Vescini F, Mazziotti G
J Neuroendocrinol · 2025 Sep · PMID 40452250 · Full text
Patients with gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may present skeletal fragility that might be related to multiple factors, including bone metastases, vitamin D deficiency, hormone secretion, and dise...
Patients with gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may present skeletal fragility that might be related to multiple factors, including bone metastases, vitamin D deficiency, hormone secretion, and disease treatments. This study examines the prevalence and determinants of fragility fractures in low grading (G1-G2) GEP-NETs. This retrospective study included 291 patients with G1-G2 GEP-NETs (154 men and 137 women). A longitudinal examination was available for 247 patients, with a median follow-up of 49 months (range 24-83). Information regarding disease course, osteo-metabolic profile, and clinical fractures were collected from electronic medical records. Opportunistic chest-abdomen computed tomography or magnetic resonance imaging scans were retrospectively examined to investigate morphometric vertebral fractures. Fracture prevalence in men over 50 and post-menopausal women (n = 200) was compared to an age-matched control sample of 1010 subjects (146 men and 864 women). Forty-five patients with GEP-NETs (15.5%) had fragility fractures at diagnosis of disease. Fractures were significantly associated with age, body mass index, comorbidities, and severe vitamin D deficiency (25(OH)vitamin D < 10 ng/mL) at univariate analysis, and to severe vitamin D deficiency (p = .03) and age (p = .01) at multivariate analysis. When compared to the control group, GEP-NETs patients were found to be independently associated with fractures (OR 2.0 IC95% [1.1-3.6], p = .02). At longitudinal evaluation, 10% of GEP-NETs experienced new fractures in relation to pre-existing fractures and surgical treatment of the tumor. This study provides first evidence that GEP-NETs may have a high risk of fragility fractures at the diagnosis of the disease. A proper and early assessment of bone health is therefore advisable in these patients.
Whole nest food restriction has persistent physiological effects in developing zebra finches.
Coutts VM, Pham K, Hoffman AJ … +1 more , Wada H
J Neuroendocrinol · 2025 Jun · PMID 40437748 · Publisher ↗
In a rapidly changing world, food resources are becoming more limited, leading to unpredictable bouts and durations of nutritional stress. Many studies indicate that developmental nutritional stress can permanently alter...
In a rapidly changing world, food resources are becoming more limited, leading to unpredictable bouts and durations of nutritional stress. Many studies indicate that developmental nutritional stress can permanently alter a suite of physiological, morphological, or behavioral traits, yet the phenotypic effects of low food supply in the environment may vary depending on the mode and degree of parental care. For example, our previous work suggests that zebra finch (Taeniopygia guttata castanotis) parents can buffer offspring from food restriction, minimizing negative effects on offspring growth, at the cost of maintaining their own body mass. To evaluate the effects of whole nest food restriction on the offspring further, we investigated short- and long-term changes in physiological and morphological traits of zebra finch young exposed to either an ad libitum diet or a 40% restricted diet as nestlings and juveniles until 60 days post-hatch. Specifically, we measured furculum fat, the adrenocortical response, and glucose levels throughout development and into adulthood as well as body mass in adulthood to examine any latent or persistent effect. Young from the food-restricted nests overall had significantly higher baseline corticosterone and glucose compared to controls, suggesting that the previously observed parental buffering may not have been sufficient to mitigate the deleterious effects of food restriction. Furthermore, food-restricted birds had lower body mass compared to controls in adulthood, suggesting that there was a latent effect that manifested in adulthood, potentially due to the physiological costs observed during treatment and the later release of treatment. Furculum fat, the glucose response, and the adrenocortical response did not differ between experimental groups. There was also no difference in brood body size variance between treatment groups, and previously observed parental compensation in food-restricted nests did not correlate with offspring body mass in adulthood. Lastly, there was a significant negative relationship between body mass and baseline corticosterone in adulthood, suggesting that although growth and body mass were maintained during treatment, energy may have been redirected from growth and body mass maintenance to different processes in adulthood. This study further supports the need for measuring traits after treatment ends to determine persistent effects of stressors and highlights that parents cannot fully buffer their offspring from adverse environmental conditions.
Dynamic changes in Ccn3 expression across the limbic forebrain through the mouse estrous cycle and during lactation.
Yeo SH, Gul Z, Zhou Z … +3 more , Muresan L, Wall EG, Herbison AE
J Neuroendocrinol · 2025 Sep · PMID 40421539 · Full text
Cellular communication network factor 3 (CCN3), also known as nephroblastoma overexpressed (NOV), is an adipocytokine that has recently been suggested to be secreted selectively by hypothalamic arcuate nucleus kisspeptin...
Cellular communication network factor 3 (CCN3), also known as nephroblastoma overexpressed (NOV), is an adipocytokine that has recently been suggested to be secreted selectively by hypothalamic arcuate nucleus kisspeptin (ARN) neurons to protect bone density during lactation. Using RNAscope hybridization, we have examined the expression of Ccn3 transcripts in the forebrain of male mice and female mice across the estrous cycle and during lactation. Transcripts for Ccn3 are highly expressed in the cerebral cortex, hippocampus, subthalamic nucleus, and amygdala in both sexes. Lower levels of Ccn3 mRNA were detected within the hypothalamus of females but not males. During lactation (day 11), a substantial 6-fold increase in the numbers of cells expressing Ccn3 mRNA was found in the arcuate and dorsomedial nuclei of the hypothalamus as well as the posterodorsal division of the medial amygdala. Approximately 50% of cells expressing Ccn3 in the ARN during lactation also contained Kiss1 transcripts. An increase in Ccn3 mRNA expression in ARN neurons also occurred during proestrus. These observations demonstrate that multiple limbic brain regions and cell types coordinately up-regulate their expression of Ccn3 during lactation in the mouse.
Sexually dimorphic distribution of Kiss1 neurons in the bed nucleus of the stria terminalis.
Zdon ST, Silva MSB, Navarro VM
J Neuroendocrinol · 2025 Aug · PMID 40421488 · Full text
Kiss1 neurons play a crucial role in reproductive function and are found in distinct brain regions, including the bed nucleus of the stria terminalis (BNST). However, the sexual dimorphism of Kiss1 neurons in the BNST an...
Kiss1 neurons play a crucial role in reproductive function and are found in distinct brain regions, including the bed nucleus of the stria terminalis (BNST). However, the sexual dimorphism of Kiss1 neurons in the BNST and their projections has not been fully characterized. This study examined the distribution and projections of Kiss1 neurons in the anterior (aBNST) and principal (prBNST) regions of the BNST in male and female Kiss1-Cre and Kiss1-Cre; tdTomato mice. Neuroanatomical analysis and tracing experiments were conducted to quantify Kiss1 neurons and map their projections. Males had approximately a threefold higher number of Kiss1 neurons in the prBNST than females, while no significant sex difference was observed in the aBNST. Viral tracing experiments revealed sexually dimorphic projections of Kiss1 neurons, with females displaying more diverse projections to various brain regions involved in reproduction and social behaviors. Kiss1 neurons project exclusively to the zona incerta and adBNST in both sexes, while females exhibited additional projections to the RP3V and PVH. The sexually dimorphic distribution and projections of Kiss1 neurons suggest their potential role in modulating sex-specific behaviors and neuroendocrine functions. This neuroanatomical sexual dimorphism may contribute to sex differences in social and reproductive behaviors associated with BNST function, providing new insights into the neural basis of sex-specific behaviors and reproductive regulation.
ISAE 2024: Exploring frontiers in avian endocrinology.
Kumar V
J Neuroendocrinol · 2025 Jun · PMID 40405343 · Publisher ↗
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The geographical distribution of neuroendocrine neoplasms in England (2012-2018).
Nwoguh CA, Asmar ME, Mortagy M … +5 more , Srirajaskanthan R, Russell B, White BE, Chandrakumaran K, Ramage JK
J Neuroendocrinol · 2025 Aug · PMID 40404336 · Publisher ↗
Neuroendocrine Neoplasms (NEN) are increasing in incidence in England over the past two decades. Geographic and socio-economic disparities influence both incidence and survival rates. This study explores the relationship...
Neuroendocrine Neoplasms (NEN) are increasing in incidence in England over the past two decades. Geographic and socio-economic disparities influence both incidence and survival rates. This study explores the relationship between environmental factors, access to specialised care in Centres of Excellence (CoE), and survival outcomes for NEN patients across England using Geographical Information Systems (GIS) to visualise disease distribution. Data on 19,958 NEN cases diagnosed between 2012 and 2018 were retrieved from the National Cancer Registry and Analysis Service (NCRAS) in England. GIS was used to analyse patient data, including spatial units, environmental factors, and travel times to CoE. Statistical analyses, including age-standardised rates, spatial autocorrelation, and survival analyses, were performed using QGIS, SPSS, R, and Stata software. Regional distribution showed the highest age-standardised rates (ASR) in the North-East, with lung NEN demonstrating significant spatial clustering. Environmental exposures, such as PM2.5 pollution, did not show a strong correlation with NEN distribution. Longer travel times to specialised centres were associated with worse overall survival, particularly in rural areas and among patients with higher socio-economic deprivation. Minor variations in survival rates were observed across different geographical regions when compared to London. This study highlights the uneven burden of disease across different regions in England. We have demonstrated variation in the country relating to anatomical sites and significant differences within rural or urban environments. Proximity to specialist centres was associated with better overall survival, highlighting the need for improved access to care.
Steroids and nervous system-2024.
Giatti S, Gotti S, Melcangi RC
J Neuroendocrinol · 2025 Jul · PMID 40400179 · Publisher ↗
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Maternal high fat and high sugar diet impacts on key DNA methylation enzymes in offspring brain in a sex-specific manner.
Hor K, Dearden L, Herzstein E … +3 more , Ozanne S, Hardingham G, Drake AJ
J Neuroendocrinol · 2025 Aug · PMID 40373797 · Full text
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 murin...
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, n = 7) or control (CON, n = 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.
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.
Helou AY, de Carvalho C, do Carmo LA … +1 more , Bittencourt JC
J Neuroendocrinol · 2025 Aug · PMID 40369718 · Full text
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 r...
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, p < .001), followed by the all-female group (20.3 ng/mL, p < .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.
The Analgesic and Antidepressant Role of Oxytocin-Containing Neurons in the Hypothalamic Paraventricular Nucleus in Mice With Spared Nerve Injury.
Wang S, Ren S, Lv S … +5 more , Liu Y, Xing K, Zhang T, Jin X, Shi J
J Neuroendocrinol · 2025 Aug · PMID 40356350 · Publisher ↗
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 (simplif...
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.
Exogenous visfatin suppresses pituitary gonadotrophins and stimulates testosterone secretion in a male mouse.
Rempuia V, Gurusubramanian G, Roy VK
J Neuroendocrinol · 2025 Aug · PMID 40350982 · Publisher ↗
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 gona...
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.
Pancreatic neuroendocrine tumors in children and adolescents-Data from the German MET studies (1997-2023).
Karges K, Kunstreich M, Pape UF … +10 more , Fuchs J, Vokuhl C, Abele M, Schneider DT, Brecht IB, Lapa C, Frühwald MC, Vorwerk P, Redlich A, Kuhlen M
J Neuroendocrinol · 2025 Aug · PMID 40350184 · Full text
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...
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, p = .0082) and complete surgical resection (R vs. R vs. no resection, p = .0077) but not with lymph node involvement (N0 vs. N1, p = .12), tumor localization within the pancreas (head vs. body vs. tail, p = .86), the extent of the primary tumor (pT1-2 vs. pT3-4, p = 1.0), pathological grade (G1 vs. G2-3, p = .28), or proliferation index (Ki67 ≤ 10% vs. >10%, p = .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.
Chronic variable mild stress alters the transcriptome and signaling properties of the anterodorsal bed nucleus of the stria terminalis in a sex-dependent manner.
Degroat TJ, Paladino SE, Samuels BA … +1 more , Roepke TA
J Neuroendocrinol · 2025 Aug · PMID 40325549 · Publisher ↗
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 dysreg...
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.
The impact of re-characterizing metastatic pancreatic neuroendocrine tumors: A prospective study.
Mollazadegan K, Botling J, Skogseid B … +7 more , Eriksson B, Falkman L, Zhang L, Lase I, Welin S, Sundin A, Crona J
J Neuroendocrinol · 2025 Aug · PMID 40325349 · Full text
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 dis...
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) (F-fluorodeoxyglucose (F-FDG) and Gallium-68 DOTATOC (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% (n = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (n = 8/16). Twelve and 15 patients were positive on F-FDG- and Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (n = 2), P2b (n = 12), and P3b (n = 1). A clinically significant change was noted among 62% (n = 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% (n = 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.
Overexpression of the short isoform of the dopamine D2 receptor causes diet-induced obesity and hyperglycemia in mice.
Gonzalez H, Cheng L, Chang Q … +3 more , Gold PE, Perez-Tilve D, Wang Y
J Neuroendocrinol · 2025 Aug · PMID 40320729 · Full text
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 cha...
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.
PRRT plus holmium-166-SIRT (HEPAR PLuS) versus PRRT-only in patients with metastatic neuroendocrine tumors: A propensity-score matched analysis.
Veldhuis WB, Walter T, de Vries-Huizing DMV … +12 more , Theysohn J, Barton S, Ekkelenkamp ED, Lachachi B, de Jong RJG, van Golen LW, Lanzafame H, Milot L, Lahner H, Lam MEGH, Tesselaar MET, Braat AJAT
J Neuroendocrinol · 2025 Aug · PMID 40302310 · Full text
Patients with bulky neuroendocrine liver metastases (NELM) undergoing PRRT with [Lu]Lu-DOTATATE have a worse survival than patients with limited liver metastases. Previously, the safety and efficacy of additional selecti...
Patients with bulky neuroendocrine liver metastases (NELM) undergoing PRRT with [Lu]Lu-DOTATATE have a worse survival than patients with limited liver metastases. Previously, the safety and efficacy of additional selective internal radiotherapy (SIRT), using holmium-166 (Ho)-microspheres, directly following PRRT in patients with NELM were confirmed in the prospective HEPAR PLuS study. The aim of the current study was to provide insight into the efficacy and survival benefit of PRRT + Ho-SIRT over PRRT-only by means of a propensity score matched historical cohort. A multicenter retrospective data collection was performed to match patients treated with PRRT-only to the prospectively collected HEPAR PLuS study patients. Demographic, clinical, laboratory, and imaging data were collected. The primary endpoint was the proportion of patients with progression-free survival (PFS) at 2 years after the start of PRRT. Secondary endpoints included the proportion of patients with 2-year hepatic PFS (hPFS), general PFS and hPFS, objective response rates (ORR), and overall survival (OS). Twenty-four patients were 1:1 matched and included in the analysis. All key matching criteria were balanced between cohorts if feasible. The proportion of patients with PFS and hPFS at 2 years was 68% and 82% after PRRT + Ho-SIRT versus 55% and 50% after PRRT only. Time to median PFS was comparable (31 vs. 30 months). An initial delay in hepatic progression or death of any cause was observed in PRRT + Ho-SIRT mNET patients (75% probability of PFS at 27 vs. 22 months), most notably in intestinal tumors (75% probability of PFS at 26 vs. 15 months). Best ORR was 71% after PRRT + Ho-SIRT versus 25% after PRRT only. This study showed that Ho-SIRT after PRRT (vs. PRRT-only) had a positive effect on the liver disease progression in patients with NELM, increasing the 2-year hPFS rate and tumor response and delaying hepatic progression or death. However, this effect did not translate into improving general PFS and OS.
Photostimulation increases food intake, agouti-related protein (AGRP) and type II iodothyronine deiodinase (DIO2) gene expression in the medio-basal hypothalamus of Gambel's White-crowned Sparrow.
Boswell T, Olson SK, Bentley GE … +2 more , Perfito N, Ramenofsky M
J Neuroendocrinol · 2025 Jun · PMID 40296442 · Full text
Before migration, birds express hyperphagia leading to deposition of fuel in support of long-distance flight. Long days in spring stimulate a photoperiodic neuroendocrine cascade leading to heightened food intake. A majo...
Before migration, birds express hyperphagia leading to deposition of fuel in support of long-distance flight. Long days in spring stimulate a photoperiodic neuroendocrine cascade leading to heightened food intake. A major component of the response of the reproductive system to increased daylength in birds is the local conversion of thyroxine (T4) to triiodothyronine (T3) in the medial basal hypothalamus. However, mechanisms of photostimulation regulating hyperphagia in migratory birds have yet to be resolved. We report results from two studies of Gambel's White-crowned Sparrow (Zonotrichia leucophrys gambelii), a long-distance migrant. We used quantitative PCR to measure basal hypothalamic gene expression of several neuropeptides, glucocorticoid receptors, type II and type III iodothyronine deiodinase enzymes (DIO2 and DIO3), and α1 and α2 subunits of the cellular energy sensor AMP-activated protein kinase (AMPKα1 and AMPKα2). The first study involved birds on short days of 9L:15D exposed to 18 h food deprivation. In the second study, birds were photostimulated by one or two long days of 20L:4D. We observed no significant effects of food deprivation on hypothalamic gene expression. However, photostimulation significantly increased food intake on the first and second long days and was associated with significant increases in agouti-related protein (AGRP) and AMPKα2 mRNAs and in the ratio of DIO2/DIO3 expression. The pattern of increased DIO2 and decreased DIO3 gene expression is likely to have increased basal hypothalamic T3 content. This, in turn, may lead to altered local AMPK signaling to increase AGRP biosynthesis and thereby promote photostimulated hyperphagia.
Neuropeptides and reproductive flexibility in songbirds: A mini review.
Tripathi V, Bhardwaj SK, Kumar V
J Neuroendocrinol · 2025 Jun · PMID 40288996 · Publisher ↗
Synchronization of physiological and behavioral activities associated with avian reproduction requires corresponding changes in the activity of the hypothalamus-pituitary-gonadal axis. This involves complex brain peptide...
Synchronization of physiological and behavioral activities associated with avian reproduction requires corresponding changes in the activity of the hypothalamus-pituitary-gonadal axis. This involves complex brain peptidergic pathways, which show spatial and temporal differences in their expression and distribution during the annual reproductive cycle. The well-studied pathways include gonadotropin-releasing and inhibiting hormones (GnRH, GnIH), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), vasoactive intestinal peptide (VIP) and other peptides like arginine vasotocin (VT), oxytocin (mesotocin), and spexin. Together, these peptides form a neurochemical framework for the integration of both internal and external (environmental) cues; this results in a neuroendocrine response. Conceivably, therefore, the neurochemical framework within which brain peptides possibly interact and perform reproductive regulatory roles might show species differences. Here, we aim to review briefly the roles of these neuropeptides in reproduction in both opportunistically and seasonally breeding birds. Much of the discussion will be based on our own research on the opportunistic breeding zebra finch and the seasonally breeding redheaded bunting, Indian weaverbird, and spotted munia. The summer breeding redheaded bunting and weaverbird are typical photosensitive long-day species, but they show qualitative differences in response to stimulatory photoperiods during the post-reproductive period of their annual cycle. Buntings exhibit absolute photorefractoriness, while weaverbirds exhibit relative photorefractoriness. The autumn breeding spotted munia, on the other hand, is an atypical photosensitive species. It responds to both short and long photoperiods and presumably lacks photorefractoriness.
Role of melatonin in physiological mitigation of sleep disruption in an unnatural temporal environment.
Buniyaadi A, Prabhat A, Bhardwaj SK … +1 more , Kumar V
J Neuroendocrinol · 2025 Aug · PMID 40268688 · Publisher ↗
Illuminated nights reduce melatonin peak and disrupt sleep. Using this as the basis of the present experimental paradigm, we investigated whether nocturnal melatonin levels were crucial for sleep regulation in a diurnal...
Illuminated nights reduce melatonin peak and disrupt sleep. Using this as the basis of the present experimental paradigm, we investigated whether nocturnal melatonin levels were crucial for sleep regulation in a diurnal vertebrate. Acclimated Indian house crows (Corvus splendens) were randomly segregated into three groups of 12 each. For the next 10 days, one group was maintained on 12 L:12 D, as before (LD control); for the other two groups, the absolute darkness was replaced with dim light at night (dLAN; L = ~150 lux, D = ~6 lux). Under dLAN, half an hour before light off time, the LD control and one dLAN group received intraperitoneally 200 μL of vehicle (0.75% physiological saline), while the other dLAN group received a similar 200 μL vehicle but containing melatonin at a dose of 50 μg bird day. Under dLAN, exogenous melatonin elevated nocturnal AANAT mRNA and plasma melatonin levels and induced changes in diurnal expressions of clock genes (PER2, CRY1, BMAL1, NPAS2, REVERB) in the pineal gland and hypothalamus, and of genes encoding melatonin receptors (MEL1a, MEL1b) and epigenetic modifiers (HAT1, HDAC2, HDAC4, DNMT3a) in the hypothalamus. Elevated nocturnal melatonin levels bettered sleep with positive effects on the hypothalamic expression of genes associated with nocturnal sleep (cytokine pathway: TLR4, TNFα, IL-1β, NOS1; calcium pathway: CAMK2, SIK3) and awake (ACHM3, EGR1, HOMER1a, OREXIN) states, and with neurogenesis and synaptic plasticity (BDNF, EGR1, CREB). These suggested the role of melatonin in mitigation of the dLAN-induced sleep disruption. Nocturnal melatonin peak levels are a crucial component of the regulatory transcriptional pathways underlying the daily wake-sleep pattern, with far-reaching implications for sleep-related issues in diurnal species including perhaps humans inhabiting an over-lit environment with pervasive light pollution.
Timing mismatches, carryover effects, and the role of neuroendocrine mechanisms in determining birds' responses to environmental change.
Hahn TP, Cornelius JM, Watts HE
J Neuroendocrinol · 2025 Jun · PMID 40268496 · Full text
The neuroendocrine system plays a critical role in the synchronization of life cycle stages with variation in the environment, and in the coordination of life cycle stages with one another. When humans modify environment...
The neuroendocrine system plays a critical role in the synchronization of life cycle stages with variation in the environment, and in the coordination of life cycle stages with one another. When humans modify environments, these neuroendocrine mechanisms may impact how different individuals, populations, species, and even communities are affected. Here we conceptualize how endocrine mechanisms may influence the likelihood of: (1) timing mismatches between life cycle stages and environmental conditions, and (2) carryover effects within annual cycles. Timing mismatches can occur when an individual fails to synchronize a particular life cycle stage to the appropriate environmental conditions. Carryover effects occur when activities of one stage (including its timing) affect the performance in one or more subsequent stages. We suggest that there is a trade-off between timing adjustments within and across stages such that neuroendocrine mechanisms that reduce timing mismatches in temporally changing environments (e.g., strong neuroendocrine responsiveness to short-term cues, with resultant increased temporal flexibility to fine-tune the current stage to local conditions) may inherently increase the likelihood of carryover effects (e.g., through delay of a transition between stages), and vice versa. We use two examples-flexibility of the onset of photorefractoriness mediated by responsiveness to short-term cues, and sensitivity of molt to sex steroids-to illustrate these ideas, and suggest that future work should investigate the impacts of variation in these and potentially other seasonal timing mechanisms on carryover effects. The conceptual framework presented here suggests that there may be no single best set of tactics for coping with the effects of climate change; species with neuroendocrine mechanisms facilitating temporal flexibility may avoid some timing mismatches but set themselves up for deleterious carryover effects as they make temporal adjustments to environmental conditions modified by climate change.
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