Journal of Neuroendocrinology最新文献

Neuroscience depends heavily on research done in mice (Mus musculus), yet the field has done little to address the chronic cold stress mice perpetually face during conventional “room temperature” housing (20°C–22°C). Contributions from other biomedical fields, such as immunology, oncology, and metabolic physiology, have shown that housing mice at room temperature substantially impacts broad and fundamental aspects of murine biology in ways that negatively affect the translational value of the research derived from these animals. Prairie voles (Microtus ochragaster) are an alternative small rodent model for neuroscience that are adapted for cold weather and better tolerate the ambient temperature of conventional housing. Here, we examined the effect of 3 days of housing at one of three ambient temperature conditions: 20°C, 25°C, or 30°C on oxytocin and vasopressin immunoreactivity within the paraventricular nucleus of the hypothalamus in both mice and voles. We found that increases in ambient temperature above 20°C led to a 32% reduction in oxytocin immunoreactivity in mice, while having no effect in voles. Vasopressin was unaffected in either species. Since oxytocin is a pleiotropic neuropeptide, responsible for regulating a number of homeostatic, emotional, and social circuits, this work calls into question whether findings from mice housed at 20°C can be reliably translated to humans living in thermoneutral conditions. This finding should spur further neuroscience research to reconcile how the assumptions of conventional housing have shaped murine neurobiology.

Prolactin is fundamental for pregnancy and lactation, and also has numerous metabolic roles including the stimulation of appetite. Mice with chronic hyperprolactinemia display increased food intake, enhanced expression of orexigenic genes in hypothalamic brain centers, and also develop obesity. Here, we tested whether the consumption of a rewarding high-fat diet (HFD) is altered in a mouse model of chronic hyperprolactinemia: LacDrd2KO mice, which lack dopamine Drd2 receptors in lactotrophs, preventing dopamine inhibition of prolactin secretion. We exposed control and LacDrd2KO mice to a binge-like eating protocol in which satiated mice have access to a HFD pellet for 2-h on four consecutive days. We found that both control and LacDrd2KO animals displayed binge-like eating of HFD, and that hyperprolactinemic mice nearly doubled their HFD intake compared to controls. Subsequently, we analyzed the activation of mesocorticolimbic brain nuclei involved in reward processing. We observed that, in response to HFD consumption, c-Fos levels were higher in dopaminergic neurons of the parabrachial pigmented area within the ventral tegmental area (VTA), a key brain center involved in reward regulation, and also in the core subdivision of the nucleus accumbens (Acb), the main target of dopaminergic VTA neurons. Furthermore, hyperprolactinemic mice had greater c-Fos activation in dopaminergic neurons of the VTA in response to HFD consumption, compared to control animals. Finally, c-Fos levels in the hypothalamic arcuate nucleus, mainly involved in the control of homeostatic food intake, were lower in LacDrd2KO mice and unaffected by HFD exposure. Current results suggest that chronic hyperprolactinemia is associated with increased consumption of a rewarding stimulus, engaging the activation of dopaminergic neurons in the VTA.

Diabetes is a significant risk factor for the development of diabetic kidney disease, and about 30% of people with type I diabetes mellitus will eventually develop end-stage kidney disease. Growth hormone (GH) and its mediator insulin-like growth factor (IGF-I) are crucial for kidney development and function in healthy conditions. However, elevated circulatory levels of GH in type I diabetes mellitus disrupt homeostasis and cause changes in the kidney's structure and function, such as hypertrophy, glomerulosclerosis, and proteinuria. Glomerular podocytes are specialized cells in the nephron, and they practically represent the kidney's filtration function. Podocytes are terminally differentiated cells, and podocyte injury or loss causes significant damage to the glomerulus manifested by varying degrees of proteinuria. Recent studies have identified that podocytes express GH receptors and are key targets of GH action, particularly in settings with type I diabetes mellitus. GH could negatively affect podocyte biology, thus potentially contributing to glomerular manifestations, kidney damage, and thereby contribute to diabetic kidney disease. GH evokes the reactivation of the embryologically active Notch signaling in adult podocytes. As a consequence, terminally differentiated podocytes undergo cell-cycle reentry. This manuscript overviews the aberrant activation of embryologically active pathways in quiescent adult podocytes, complications of cell-cycle reentry, aberrations in cytokinesis, and consequent mitosis-associated cell death.

Early detection of metastases and timely surgical intervention play a crucial role in the management of neuroendocrine tumors. In large-sized pheochromocytomas and sympathetic paragangliomas (PPGL), functional imaging with positron emission tomography (PET) is recommended, as it improves the detection of metastases, which may go undetected on conventional radiologic imaging. ¹¹C-hydroxyephedrine binds to the norepinephrine transporter receptor and is detected by PET/CT (HED-PET/CT). It has previously demonstrated high accuracy in detecting primary and metastatic PPGL; however, its impact on preoperative staging is unclear. In this study, we retrospectively analyzed a selected cohort of 44 patients with large PPGL to evaluate whether HED-PET/CT influences preoperative clinical decision-making. All patients who underwent HED-PET/CT at Uppsala University Hospital between 2004 and 2024 were screened for inclusion. In total, 44 patients with pheochromocytomas >5 cm and paragangliomas >4 cm were included. HED-PET/CT results were compared with CT/MR findings, and a final consensus was reached on whether preoperative HED-PET/CT would have altered clinical decision-making. HED-PET/CT identified previously undetected metastatic disease in three patients (6.8%), which had not been visualized on CT/MR. Additionally, two patients had discordant findings, where HED-PET/CT revealed additional metastases. In one case, a liver metastasis was identified postoperatively with HED-PET/CT, leading to a metastasectomy that could have potentially been avoided. These findings suggest that HED-PET/CT is highly accurate in detecting metastases; however, its routine preoperative use may be limited and appears to provide significant clinical benefit only in selected patients.

Miscarriage, defined as spontaneous pregnancy loss before 20 weeks of gestation, affects 10–15% of pregnancies in women under 30, rising to over 50% in women over 45. Implantation failure and early placental dysfunction are major contributors, yet the precise mechanisms remain incompletely understood. Kisspeptin, encoded by KISS1, is a critical regulator of the reproductive axis and is highly expressed in the placenta, where it modulates trophoblast proliferation, migration, invasion, and vascular remodelling. Human studies indicate that reduced placental kisspeptin is associated with recurrent pregnancy loss, while circulating kisspeptin levels increase dramatically throughout gestation and may serve as a biomarker for pregnancy viability. Mouse models, including CBA/J × DBA/2 matings and Kiss1/Kiss1r knockout lines, have provided mechanistic insights, showing that loss of kisspeptin signalling impairs decidualization, trophoblast invasion, and embryo implantation. These studies also highlight kisspeptin's role in modulating maternal immune responses and in coordinating hormonal cues, including progesterone, oestrogen, and prolactin, necessary for uterine receptivity. Despite shared features of placentation signal and endocrine regulation, significant species-specific differences exist (e.g. mice lack hCG, exhibit embryo-dependent decidualization, have less invasive trophoblasts) limiting direct extrapolation to human pregnancy. This review synthesizes current evidence on kisspeptin's paracrine and endocrine roles during early gestation, emphasizing the insights gained from murine models while highlighting the translational challenges in applying these findings to human miscarriage research.

Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix proteins and occurs in a variety of cardiac diseases, such as the highly prevalent syndrome heart failure with preserved ejection fraction (HFpEF) and other cardiac disorders. Interstitial fibrosis has been identified as a central pathophysiological factor induced and maintained by metabolic stress and chronic inflammation. Considering the limited treatment options for cardiac fibrosis, new therapeutic targets are urgently needed. Mounting evidence for the cardioprotective effects of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) provides a rationale to elucidate its role and that of its receptor PAC1 in metabolic stress-mediated cardiac fibrosis. Metabolic stress was induced by feeding a cholesterol-enriched diet (CED) to PACAP^−/−/ApoE^−/−, PAC1^−/−/ApoE^−/− and ApoE^−/− mice and cardiac tissue subjected to analyses of fibrosis. Under CED feeding, a statistically significant (p < .001) increase in myocardial fibrosis was observed in PACAP^−/−/ApoE^−/− and PAC1^−/−/ApoE^−/− compared to ApoE^−/− mice. These findings suggest a role for PACAP signaling in the mitigation of metabolically induced cardiac fibrosis. The antifibrotic effect of PACAP is dependent on the expression of the PAC1 receptor and only emerges under metabolic stress conditions. PAC1 receptor agonists may have the potential to attenuate metabolically triggered cardiac fibrosis arising after a chronic high-fat diet.

Bone metastases (BMs) were reported in <15% of cases of neuroendocrine neoplasms (NENs). Their clinical behavior is various and clinical management is still undefined. This study aimed to describe the clinical practical management and survival outcome of neuroendocrine neoplasm patients with BMs. This is a retrospective, observational, multicenter, nationwide study, in which clinical-pathological characteristics, diagnostic tools, skeletal-related events (SREs), bone targeted agents (BTAs) and their correlation with clinical outcome were collected. Data from 320 patients from 18 Italian centers diagnosed with bone metastases during 2000–2013 were captured. Most patients had a well/moderately differentiated NEN, with synchronous distant metastases, mostly hepatic, the majority of which originated from a gastroenteropancreatic primary site. Bone was the first metastatic site in 41% of patients. After a median follow-up of 27 months 122 patients died. The median overall survival (OS) was 62 months. In 22% of patients (n = 72), SREs were observed, and 31% of patients received a BTA. At multivariable analysis of factors associated with OS after the development of BMs, primary lung site, Ki-67 ≥55% versus ≤20%, >10 BMs, mixed pattern (osteoblastic/osteolytic) versus osteoblastic, prior lung metastases and SREs were found to be significant poor prognosis factors. At multivariable analysis Ki-67 ≥55% versus ≤20% remains significantly associated with the development of SREs. Our study represents a real-life nationwide scenario of a large series of NEN patients with BMs handled at dedicated centers. Several hypotheses generated by this study are warranted to be tested in future homogeneous studies, including objective criteria for the use of BTAs.

The neuroendocrine control of growth is mediated by the hypothalamic–pituitary–somatic (HPS) axis. This involves the hypothalamic release of growth hormone-releasing hormone (GHRH), which stimulates the pituitary secretion of growth hormone (GH). GH subsequently promotes growth both directly and indirectly by stimulating insulin-like growth factor 1 (IGF1) release from the liver. While extensive research has focused on the actions and mechanisms of GH and IGF1, comparatively little attention has been given to how GHRH neurons themselves are regulated. This review aims to provide insight into how GHRH neurons are controlled, emphasizing their intrinsic electrophysiological properties and the broader brain circuitry involved in detecting physiological signals such as hormonal and metabolic status. Central to this regulation is the balance of excitatory and inhibitory inputs that generate the pulsatile secretion pattern essential for growth regulation. Somatostatin (SST) provides critical inhibitory control over both GH secretion and GHRH neuronal activity. Feedback from peripheral hormones and integration of environmental and metabolic cues can further shape GHRH neuron function. Developmental, sex-dependent, and species-specific variations in GHRH neuron regulation are also discussed, highlighting important avenues for future research. This review offers a neuroendocrine perspective on growth regulation, with important implications for understanding the brain's role in regulating growth and development.

How neuropeptides act within the neural circuits that control social behavior is not well understood. While the prevailing view is that neuropeptides act through synaptic release and then activation of their canonical receptors on postsynaptic membranes, we investigated the role of a very different form of neuropeptide action in a neural circuit regulating social communication. Specifically, we tested the hypothesis that non-synaptically released oxytocin (OT) can act via the non-canonical receptors vasopressin V1a receptors (V1aR) to regulate social communication in Syrian hamsters. Scent marking, a key form of hamster social communication, can be enhanced by the α-melanocortin stimulating hormone (α-MSH), which stimulates OT but not arginine-vasopressin (AVP) release. Here, we employed hypothalamic injections of α-MSH and the α-MSH MC4R receptor antagonist MCL-0020 to determine the role of α-MSH in the expression of flank marking. To determine if these effects were intracellular calcium (iCa²⁺) dependent, hamsters were injected with AVP to induce flank marking and with the iCa²⁺ antagonist TMB-8 to test whether it was possible to block this behavioral effect. Further, a highly selective AVP V1a receptor (V1aR) antagonist and an OT receptor (OTR) antagonist were injected into the hypothalamus to investigate the receptor responsible for activating flank marking. Finally, we employed an in vitro hypothalamic slice preparation using “Sniffer cells” biosensors to confirm that α-MSH induced the release of OT but not AVP. First, we found that the in vivo hypothalamic injection of α-MSH increased odor-stimulated scent marking, whereas blockade of its receptor with MCL-0020 reduced this behavior. Hypothalamic infusion of the iCa²⁺ antagonist TMB-8 significantly reduced both AVP-induced and α-MSH-induced flank marking. Moreover, only the V1aR antagonist, and not the OTR antagonist, significantly decreased scent marking in response to hypothalamic infusion of α-MSH. Finally, biosensor recordings from hypothalamic slices confirmed that α-MSH stimulates OT, but not AVP, release. Together, these results demonstrate that α-MSH triggers non-synaptic OT release that regulates scent marking via V1aR activation, revealing a novel mechanism by which neuropeptides modulate social behavior.