Should We Make More Bone or Not, As Told by Kisspeptin Neurons in the Arcuate Nucleus

Abstract

Since its initial discovery in 2002, the neuropeptide Kisspeptin (Kiss1) has been anointed as the master regulator controlling the onset of puberty in males and females. Over the last several years, multiple groups found that Kiss1 signaling is mediated by the 7TM surface receptor GPCR54. Kiss1 mRNA is highly enriched in the basal medial and lateral subregions of the arcuate nucleus (ARC) in the medial basal hypothalamus. Thus, Kiss1^ARC neurons reside in a unique anatomical location ideal for sensing and responding to circulating steroid hormones as well as nutrients. Kiss1 expression is highly responsive to fluctuations of the gonadal hormone, estrogen, with nearly 90% of Kiss1^ARC neurons expressing the nuclear hormone estrogen receptor alpha (ERa). Here we review recent research that extends the function of Kiss1ARC neurons beyond the regulation of puberty and highlight their emerging, novel roles in controlling energy allocation, behavioral outputs, and sex-dependent bone remodeling in females. Indeed, some of these previously unknown functions for Kiss1 neurons are quite striking as exemplified by the remarkable increase in bone mass after manipulating estrogen signaling in Kiss1^ARC neurons. Taken together, we suggest that Kiss1^ARC neurons are highly sensitive to nutritional and hormonal cues that dictate energy utilization and reproduction.

Keywords

kisspeptin - estrogen - arcuate nucleus - bone

• References

• 1 Clarkson J, d'Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 2008; 28 (35) 8691-8697
• 2 Clarkson J, Han SK, Liu X, Lee K, Herbison AE. Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol Cell Endocrinol 2010; 324 (1-2): 45-50
• 3 d'Anglemont de Tassigny X, Fagg LA, Dixon JP. , et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A 2007; 104 (25) 10714-10719
• 4 Mayer C, Boehm U. Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat Neurosci 2011; 14 (06) 704-710
• 5 Messager S, Chatzidaki EE, Ma D. , et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 2005; 102 (05) 1761-1766
• 6 Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009; 29 (38) 11859-11866
• 7 Ree HJ, Hsu SM. Lectin histochemistry of malignant tumors. I. Peanut agglutinin (PNA) receptors in follicular lymphoma and follicular hyperplasia: an immunohistochemical study. Cancer 1983; 51 (09) 1631-1638
• 8 Stafford LJ, Xia C, Ma W, Cai Y, Liu M. Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res 2002; 62 (19) 5399-5404
• 9 Hellier V, Brock O, Candlish M. , et al. Female sexual behavior in mice is controlled by kisspeptin neurons. Nat Commun 2018; 9 (01) 400
• 10 Herber CB, Krause WC, Wang L. , et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nat Commun 2019; 10 (01) 163
• 11 Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD. A neural circuit underlying the generation of hot flushes. Cell Rep 2018; 24 (02) 271-277
• 12 Qiu J, Rivera HM, Bosch MA. , et al. Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females. eLife 2018; 7: e35656
• 13 Telegdy G, Adamik Á. The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters. Behav Brain Res 2013; 243: 300-305
• 14 Kumar D, Candlish M, Periasamy V, Avcu N, Mayer C, Boehm U. Specialized subpopulations of kisspeptin neurons communicate with GnRH neurons in female mice. Endocrinology 2015; 156 (01) 32-38
• 15 Kumar D, Freese M, Drexler D, Hermans-Borgmeyer I, Marquardt A, Boehm U. Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero. J Neurosci 2014; 34 (10) 3756-3766
• 16 Yeo SH, Kyle V, Blouet C, Jones S, Colledge WH. Mapping neuronal inputs to Kiss1 neurons in the arcuate nucleus of the mouse. PLoS One 2019; 14 (03) e0213927
• 17 Yip SH, Boehm U, Herbison AE, Campbell RE. Conditional viral tract tracing delineates the projections of the distinct kisspeptin neuron populations to gonadotropin-releasing hormone (GnRH) neurons in the mouse. Endocrinology 2015; 156 (07) 2582-2594
• 18 Clarkson J, Boon WC, Simpson ER, Herbison AE. Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 2009; 150 (07) 3214-3220
• 19 Gottsch ML, Navarro VM, Zhao Z. , et al. Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways. J Neurosci 2009; 29 (29) 9390-9395
• 20 Cravo RM, Frazao R, Perello M. , et al. Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS One 2013; 8 (03) e58698
• 21 Frazao R, Dungan Lemko HM, da Silva RP. , et al. Estradiol modulates Kiss1 neuronal response to ghrelin. Am J Physiol Endocrinol Metab 2014; 306 (06) E606-E614
• 22 Martin C, Navarro VM, Simavli S. , et al. Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone. J Neurosci 2014; 34 (17) 6047-6056
• 23 Wang L, Burger LL, Greenwald-Yarnell ML, Myers Jr MG, Moenter SM. Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice. J Neurosci 2018; 38 (05) 1061-1072
• 24 Forbes S, Li XF, Kinsey-Jones J, O'Byrne K. Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neurosci Lett 2009; 460 (02) 143-147
• 25 Mayer C, Acosta-Martinez M, Dubois SL. , et al. Timing and completion of puberty in female mice depend on estrogen receptor alpha-signaling in kisspeptin neurons. Proc Natl Acad Sci U S A 2010; 107 (52) 22693-22698
• 26 Farman HH, Windahl SH, Westberg L. , et al. Female mice lacking estrogen receptor-α in hypothalamic proopiomelanocortin (POMC) neurons display enhanced estrogenic response on cortical bone mass. Endocrinology 2016; 157 (08) 3242-3252
• 27 Ohlsson C, Engdahl C, Börjesson AE. , et al. Estrogen receptor-α expression in neuronal cells affects bone mass. Proc Natl Acad Sci U S A 2012; 109 (03) 983-988
• 28 Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res 2010; 1364: 129-138
• 29 Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and metabolism: the brain and beyond. Front Endocrinol (Lausanne) 2018; 9: 145
• 30 Ducy P, Amling M, Takeda S. , et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100 (02) 197-207
• 31 Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006; 18 (04) 298-303
• 32 Bartell SM, Rayalam S, Ambati S. , et al. Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res 2011; 26 (08) 1710-1720
• 33 Padilla SL, Qiu J, Nestor CC. , et al. AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc Natl Acad Sci U S A 2017; 114 (09) 2413-2418
• 34 Kim JG, Sun BH, Dietrich MO. , et al. AgRP neurons regulate bone mass. Cell Rep 2015; 13 (01) 8-14
• 35 Sanz E, Quintana A, Deem JD, Steiner RA, Palmiter RD, McKnight GS. Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. J Neurosci 2015; 35 (14) 5549-5556
• 36 Feng Y, Manka D, Wagner KU, Khan SA. Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A 2007; 104 (37) 14718-14723
• 37 Li X, Ominsky MS, Niu QT. , et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008; 23 (06) 860-869
• 38 Liu P, Ji Y, Yuen T. , et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 2017; 546 (7656): 107-112
• 39 Sun L, Peng Y, Sharrow AC. , et al. FSH directly regulates bone mass. Cell 2006; 125 (02) 247-260
• 40 Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky A, Seeman E. The differing tempo of growth in bone size, mass, and density in girls is region-specific. J Clin Invest 1999; 104 (06) 795-804
• 41 Wang Q, Cheng S, Alén M, Seeman E. ; Finnish Calex Study Group. Bone's structural diversity in adult females is established before puberty. J Clin Endocrinol Metab 2009; 94 (05) 1555-1561
• 42 Shim KS. Pubertal growth and epiphyseal fusion. Ann Pediatr Endocrinol Metab 2015; 20 (01) 8-12
• 43 Son HE, Kim KM, Kim EJ, Jang WG. Kisspeptin-10 (KP-10) stimulates osteoblast differentiation through GPR54-mediated regulation of BMP2 expression and activation. Sci Rep 2018; 8 (01) 2134
• 44 Winslow MM, Pan M, Starbuck M. , et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 2006; 10 (06) 771-782
• 45 Brommage R, Liu J, Hansen GM. , et al. High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes. Bone Res 2014; 2: 14034