Sexually Dimorphic Glutamatergic Control of R-Spondin 1 and R-Spondin 3 Neurons in Hypothalamic Reproductive and Metabolic Nuclei
5 affiliations
- 1Department of Histology and Embryology, Faculty of Medicine, Bursa Uludag University, Bursa 16059, Türkiye
- 2Department of Histology and Embryology, Faculty of Medicine, Canakkale Onsekiz Mart University, Çanakkale 17020, Türkiye
- 3Department of Medical Pharmacology, Faculty of Medicine, Dokuz Eylul University, İzmir 35340, Türkiye
- 4Department of Biochemistry, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa 16059, Türkiye
- 5Department of Veterinary Physiology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa 16059, Türkiye
Abstract
R-spondin 1 (RSPO1) and R-spondin 3 (RSPO3) contribute to reproductive development and feeding regulation, but their hypothalamic glutamatergic regulation remains unclear. We hypothesized that NMDA and non-NMDA receptor mechanisms contribute to hypothalamic RSPO neuronal activation. Given steroid-sensitive hypothalamic glutamatergic signaling, we compared activation and antagonist-mediated attenuation between sexes. Adult male and metestrous female Sprague–Dawley rats received kainic acid or AMPA with or without CNQX pretreatment, or NMDA with or without MK-801 pretreatment. RSPO/c-Fos labeling assessed activation in the supraoptic (SON), paraventricular (PVN), and arcuate (ARC) nuclei; ELISA assessed accompanying changes in serum RSPO concentrations. All agonists activated both populations in all nuclei. Only kainate-induced PVN RSPO3 activation differed between sexes (females, 89.3%; males, 72.8%; unadjusted p = 0.039), an isolated finding among 18 agonist comparisons. Antagonists attenuated all responses, although activation remained above control in 17 of 36 conditions. Females showed greater attenuation in selected kainate and NMDA conditions in the SON and PVN. Serum changes did not parallel neuronal activation. These findings support NMDA and non-NMDA receptor involvement and sex-dependent attenuation of RSPO neuronal activation. Given the central feeding effects of RSPOs, their sex-dependent glutamatergic regulation within neuroendocrine nuclei may contribute to sex differences in metabolic control.
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BibTeX
@article{topal2026sexually,
title = {{Sexually Dimorphic Glutamatergic Control of R-Spondin 1 and R-Spondin 3 Neurons in Hypothalamic Reproductive and Metabolic Nuclei}},
author = {Gonca Topal and Duygu Gok Yurtseven and Nursel Hasanoglu Akbulut and Zulfiye Gul and Duygu Udum and Murat Yalcin and Ozhan Eyigor},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209026},
url = {https://www.mdpi.com/1422-0067/27/20/9026},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sexually Dimorphic Glutamatergic Control of R-Spondin 1 and R-Spondin 3 Neurons in Hypothalamic Reproductive and Metabolic Nuclei
AU - Gonca Topal
AU - Duygu Gok Yurtseven
AU - Nursel Hasanoglu Akbulut
AU - Zulfiye Gul
AU - Duygu Udum
AU - Murat Yalcin
AU - Ozhan Eyigor
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209026
UR - https://www.mdpi.com/1422-0067/27/20/9026
AB - R-spondin 1 (RSPO1) and R-spondin 3 (RSPO3) contribute to reproductive development and feeding regulation, but their hypothalamic glutamatergic regulation remains unclear. We hypothesized that NMDA and non-NMDA receptor mechanisms contribute to hypothalamic RSPO neuronal activation. Given steroid-sensitive hypothalamic glutamatergic signaling, we compared activation and antagonist-mediated attenuation between sexes. Adult male and metestrous female Sprague–Dawley rats received kainic acid or AMPA with or without CNQX pretreatment, or NMDA with or without MK-801 pretreatment. RSPO/c-Fos labeling assessed activation in the supraoptic (SON), paraventricular (PVN), and arcuate (ARC) nuclei; ELISA assessed accompanying changes in serum RSPO concentrations. All agonists activated both populations in all nuclei. Only kainate-induced PVN RSPO3 activation differed between sexes (females, 89.3%; males, 72.8%; unadjusted p = 0.039), an isolated finding among 18 agonist comparisons. Antagonists attenuated all responses, although activation remained above control in 17 of 36 conditions. Females showed greater attenuation in selected kainate and NMDA conditions in the SON and PVN. Serum changes did not parallel neuronal activation. These findings support NMDA and non-NMDA receptor involvement and sex-dependent attenuation of RSPO neuronal activation. Given the central feeding effects of RSPOs, their sex-dependent glutamatergic regulation within neuroendocrine nuclei may contribute to sex differences in metabolic control.
SN - 1422-0067
ER -