Role of neurokinin B in the control of female puberty and its modulation by metabolic status - PubMed (original) (raw)
Comparative Study
. 2012 Feb 15;32(7):2388-97.
doi: 10.1523/JNEUROSCI.4288-11.2012.
Francisco Ruiz-Pino, Miguel A Sánchez-Garrido, David García-Galiano, Samuel J Hobbs, María Manfredi-Lozano, Silvia León, Susana Sangiao-Alvarellos, Juan M Castellano, Donald K Clifton, Leonor Pinilla, Robert A Steiner, Manuel Tena-Sempere
Affiliations
- PMID: 22396413
- PMCID: PMC3567461
- DOI: 10.1523/JNEUROSCI.4288-11.2012
Comparative Study
Role of neurokinin B in the control of female puberty and its modulation by metabolic status
Víctor M Navarro et al. J Neurosci. 2012.
Abstract
Human genetic studies have revealed that neurokinin B (NKB) and its receptor, neurokinin-3 receptor (NK3R), are essential elements for normal reproduction; however, the precise role of NKB-NK3R signaling in the initiation of puberty remains unknown. We investigated here the regulation of Tac2 and Tacr3 mRNAs (encoding NKB and NK3R, respectively) in female rats and demonstrated that their hypothalamic expression is increased along postnatal maturation. At puberty, both genes were widely expressed throughout the brain, including the lateral hypothalamic area and the arcuate nucleus (ARC)/medial basal hypothalamus, where the expression of Tacr3 increased across pubertal transition. We showed that central administration of senktide (NK3R agonist) induced luteinizing hormone (LH) secretion in prepubertal and peripubertal females. Conversely, chronic infusion of an NK3R antagonist during puberty moderately delayed the timing of vaginal opening (VO) and tended to decrease LH levels. The expression of NKB and its receptor was sensitive to changes in metabolic status during puberty, as reflected by a reduction in Tacr3 (and, to a lesser extent, Tac2) expression in the ARC after a 48 h fast. Yet, acute LH responses to senktide in pubertal females were preserved, if not augmented, under fasting conditions, suggesting sensitization of the NKB-NK3R-gonadotropin-releasing hormone signaling pathway under metabolic distress. Moreover, repeated administration of senktide to female rats with pubertal arrest due to chronic undernutrition rescued VO (in ∼50% of animals) and potently elicited LH release. Altogether, our observations suggest that NKB-NK3R signaling plays a role in pubertal maturation and that its alterations may contribute to pubertal disorders linked to metabolic stress and negative energy balance.
Figures
Figure 1.
A, B, Developmental profiles in the expression of Tac2 (A) and Tacr3 (B) in the hypothalamus of the female rat. Values represent the percentage of the lowest value (100%) measured by real-time RT-PCR and normalized to the S11 ribosomal protein mRNA. Groups with different superscript letters and asterisks are statistically different from one another (p < 0.05, by one-way ANOVA followed by Student–Newman–Keuls multiple range test and unpaired Student's t test).
Figure 2.
Schematic representation of the distribution of Tac2 and Tacr3 mRNAs in the brain of late-infantile (P20) and pubertal (P36) female rats. AHN, Anterior hypothalamic nucleus; BLA, basolateral amygdalar nucleus; BMA, basomedial amygdalar nucleus; LM, lateral mammilary nucleus; LV, lateral ventricle; MH, medial habenula; PH, posterior hypothalamic nucleus; PVH, periventricular hypothalamic nucleus; RSP, retroesplenial area; RT, reticular nucleus thalamus; SO, supraoptic nucleus; STN, subthalamic nucleus; ZI, zona incerta.
Figure 3.
A–C, Profile of expression of Kiss1 (A), Tac2 (B), and Tacr3 (C) expression in specific hypothalamic nuclei of late-infantile (20-d-old) vs pubertal (36-d-old) female rats. Data are presented as total mRNA (number of cells × grains/cell) assessed by in situ hybridization. *p < 0.05, by unpaired Student's t test within each nucleus.
Figure 4.
A, B, Serum LH levels in prepubertal 25-d-old (A) and adult female rats in diestrus-1 (B), at 0, 20, and 60 min after central intracerebroventricular administration of vehicle or 600 pmol/rat senktide. In addition to the profiles of mean LH levels in the experimental groups, the integrated secretory responses, as the AUC over the study period (60 min), are shown (in the inset as a bar graph). **p < 0.01 versus corresponding vehicle-injected controls (one-way ANOVA followed by Student–Newman–Keuls multiple range test or unpaired Student's t test; the latter for AUC data). Veh, Vehicle; Senk, senktide.
Figure 5.
Compilation of indices of pubertal maturation recorded in immature female rats chronically intracerebroventricular injected 3 nmol of SB222200 (NK3R antagonist) or vehicle. SB222200 was injected every 12 h between P28 and P36. Dates of vaginal opening (expressed as a percentage of the total number of animals per experimental group) are shown in the left panels. Data on body and uterus weights, as well as serum LH levels, in vehicle- and SB222200-injected animals are shown in the right panels. Values are the mean ± SEM. Veh, Vehicle; ANT, antagonist; BW, body weight; UW, uterus weight.
Figure 6.
A–C, Effect of 48 h fasting on the total mRNA levels of Kiss1 (A), Tac2 (B), and Tacr3 (C) in specific hypothalamic nuclei of pubertal (36-d-old) female rats. *p < 0.05, by unpaired Student's t test within each nucleus.
Figure 7.
A, B, Serum LH levels in pubertal 36-d-old female rats fed ad libitum (A) or subjected to 48 h of fasting (B) at 0, 20, and 60 min after central intracerebroventricular administration of vehicle or 600 pmol/rat senktide in a 10 μl volume. In addition to the profiles of mean LH levels in the experimental groups, the integrated secretory responses, reported as the AUC over the study period (60 min), are shown. **p < 0.01 versus corresponding vehicle-injected controls (one-way ANOVA followed by Student–Newman–Keuls multiple range test or unpaired Student's t test; the latter for AUC data). Veh, Vehicle; Senk, senktide.
Figure 8.
Compilation of indices of pubertal maturation recorded in peripubertal female rats subjected to a protocol of 30% restriction in daily food intake (UN; 70% food intake of controls), and chronically intracerebroventricularly injected with senktide (600 pmol/12 h) or vehicle between P30 and P37. For reference purposes, data from control females fed ad libitum and injected with vehicle are also shown. Dates of VO, expressed as the percentage over the total number of animals per each experimental group, are shown in the left panel. To note, although undernutrition prevented VO in all vehicle-injected animals, senktide administration was able to restore canalization of the vagina in ∼50% of cases. Body and uterus weight records in the different experimental groups at the end of the treatment are presented in the right panels. In addition, senktide treatment significantly elevated serum LH levels. ¶p < 0.01 vs controls fed ad libitum; **p < 0.01 versus UN rats injected with vehicle (one-way ANOVA followed by Student–Newman–Keuls multiple range test). Veh, Vehicle; Senk, senktide; BW, body weight; UW, uterus weight.
Similar articles
- Neurokinin B and the control of the gonadotropic axis in the rat: developmental changes, sexual dimorphism, and regulation by gonadal steroids.
Ruiz-Pino F, Navarro VM, Bentsen AH, Garcia-Galiano D, Sanchez-Garrido MA, Ciofi P, Steiner RA, Mikkelsen JD, Pinilla L, Tena-Sempere M. Ruiz-Pino F, et al. Endocrinology. 2012 Oct;153(10):4818-29. doi: 10.1210/en.2012-1287. Epub 2012 Jul 20. Endocrinology. 2012. PMID: 22822161 Free PMC article. - Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1.
Gill JC, Navarro VM, Kwong C, Noel SD, Martin C, Xu S, Clifton DK, Carroll RS, Steiner RA, Kaiser UB. Gill JC, et al. Endocrinology. 2012 Oct;153(10):4883-93. doi: 10.1210/en.2012-1529. Epub 2012 Aug 14. Endocrinology. 2012. PMID: 22893725 Free PMC article. - Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat.
Navarro VM, Castellano JM, McConkey SM, Pineda R, Ruiz-Pino F, Pinilla L, Clifton DK, Tena-Sempere M, Steiner RA. Navarro VM, et al. Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E202-10. doi: 10.1152/ajpendo.00517.2010. Epub 2010 Nov 2. Am J Physiol Endocrinol Metab. 2011. PMID: 21045176 Free PMC article. - Neurokinin B and the hypothalamic regulation of reproduction.
Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA. Rance NE, et al. Brain Res. 2010 Dec 10;1364:116-28. doi: 10.1016/j.brainres.2010.08.059. Epub 2010 Aug 25. Brain Res. 2010. PMID: 20800582 Free PMC article. Review. - Role of neurokinin B in ovine puberty.
Bedenbaugh MN, Bowdridge EC, Hileman SM. Bedenbaugh MN, et al. Domest Anim Endocrinol. 2020 Oct;73:106442. doi: 10.1016/j.domaniend.2020.106442. Epub 2020 Jan 28. Domest Anim Endocrinol. 2020. PMID: 32209283 Review.
Cited by
- Alternate-day fasting delays pubertal development in normal-weight mice but prevents high-fat diet-induced obesity and precocious puberty.
Ullah R, Xue C, Wang S, Qin Z, Rauf N, Zhan S, Khan NU, Shen Y, Zhou YD, Fu J. Ullah R, et al. Nutr Diabetes. 2024 Oct 4;14(1):82. doi: 10.1038/s41387-024-00335-w. Nutr Diabetes. 2024. PMID: 39366955 Free PMC article. - NK3R signalling in the posterodorsal medial amygdala is involved in stress-induced suppression of pulsatile LH secretion in female mice.
Ivanova D, Voliotis M, Tsaneva-Atanasova K, O'Byrne KT, Li XF. Ivanova D, et al. J Neuroendocrinol. 2024 May;36(5):e13384. doi: 10.1111/jne.13384. Epub 2024 Mar 22. J Neuroendocrinol. 2024. PMID: 38516965 Free PMC article. - Postweaning Social Isolation Alters Puberty Onset by Suppressing Electrical Activity of Arcuate Kisspeptin Neurons.
Agus S, Yavuz Y, Atasoy D, Yilmaz B. Agus S, et al. Neuroendocrinology. 2024;114(5):439-452. doi: 10.1159/000535721. Epub 2024 Jan 25. Neuroendocrinology. 2024. PMID: 38271999 Free PMC article. - Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity.
Wojtas MN, Diaz-González M, Stavtseva N, Shoam Y, Verma P, Buberman A, Izhak I, Geva A, Basch R, Ouro A, Perez-Benitez L, Levy U, Borcel E, Nuñez Á, Venero C, Rotem-Dai N, Veksler-Lublinsky I, Knafo S. Wojtas MN, et al. Mol Psychiatry. 2024 Mar;29(3):686-703. doi: 10.1038/s41380-023-02361-z. Epub 2023 Dec 22. Mol Psychiatry. 2024. PMID: 38135756 Free PMC article. - New methods to investigate the GnRH pulse generator.
Ivanova D, O'Byrne KT. Ivanova D, et al. J Mol Endocrinol. 2024 Jan 11;72(2):e230079. doi: 10.1530/JME-23-0079. Print 2024 Feb 1. J Mol Endocrinol. 2024. PMID: 38085702 Free PMC article. Review.
References
- Amstalden M, Coolen LM, Hemmerle AM, Billings HJ, Connors JM, Goodman RL, Lehman MN. Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones. J Neuroendocrinol. 2010;22:1–12. - PMC - PubMed
- Bentsen AH, Ansel L, Simonneaux V, Tena-Sempere M, Juul A, Mikkelsen JD. Maturation of kisspeptinergic neurons coincides with puberty onset in male rats. Peptides. 2010;31:275–283. - PubMed
- Castellano JM, Navarro VM, Fernández-Fernández R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146:3917–3925. - PubMed
- Castellano JM, Navarro VM, Fernández-Fernández R, Castano JP, Malagon MM, Aguilar E, Dieguez C, Magni P, Pinilla L, Tena-Sempere M. Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat. Mol Cell Endocrinol. 2006;257–258:75–83. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 HD049651-07/HD/NICHD NIH HHS/United States
- U54HD12629/HD/NICHD NIH HHS/United States
- R01 HD049651/HD/NICHD NIH HHS/United States
- U54 HD012629/HD/NICHD NIH HHS/United States
- R01 HD 049651/HD/NICHD NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources