Disparate Changes in Kisspeptin and Neurokinin B Expression in the Arcuate Nucleus After Sex Steroid Manipulation Reveal Differential Regulation of the Two KNDy Peptides in Rats

Abstract

Kisspeptin, neurokinin B (NKB) and dynorphin A are coexpressed in a population of neurons in the arcuate nucleus (ARC), termed KNDy neurons, which were recently recognized as important elements for the generation of GnRH pulses. However, the topographic distribution of these peptides and their regulated expression by sex steroids are still not well understood. In this study, detailed examination of NKB and kisspeptin immunoreactivity in the rat ARC was carried out, including comparison between sexes, with and without sex steroid replacement. Neurons expressing kisspeptin and NKB were more prominent in the caudal ARC of females, whereas neurons expressing NKB, but not kisspeptin, were the most abundant in the male. Sex steroid manipulation revealed differential regulation of kisspeptin and NKB; although kisspeptin immunoreactive (ir) cells increased in response to gonadectomy, NKB remained unchanged. Furthermore, the number of NKB-ir cells increased upon sex steroid replacement compared with gonadectomy, whereas kisspeptin did not, suggesting that sex steroids differently regulate these peptides. In addition, only in females did the density of kisspeptin- and NKB-ir fibers in the ARC increase upon sex steroid replacement in relation to sham and ovariectomy, respectively, suggesting sex-specific regulation of release. In conclusion, our observations reveal sex differences in the number of kisspeptin- and NKB-ir cells, which are more prominent in the caudal ARC. The divergent regulation of kisspeptin and NKB peptide contents in the ARC as a function of sex and steroid milieu enlarge our understanding on how these neuropeptides are posttranscriptionally regulated in KNDy neurons.

High‐fat diet and type 2 diabetes induced disruption of the oestrous cycle and alteration of hormonal profiles, but did not affect subpopulations of KNDy neurones in female rats

“…Gonadectomy with oestradiol replacement (GDX+E 2 ), however, induced no significant changes in the number of kisspeptin‐IR neurones. On the other hand, there was an effect of GDX+E 2 on the optic density of kisspeptin‐IR fibres in the ARC of females but not in males . Brown et al also revealed an increase in the hypothalamic Kiss1 mRNA after GDX and these were reversed by steroid treatment both in male and female rats, a finding also previously reported in mice .…”

“…Kisspeptin neurones are sensitive to the sex steroid milieu in a sexually dimorphic manner. Overgaard et al found that the number of kisspeptin‐IR cells in the ARC increased after gonadectomy in both male and female Wistar rats. They observed a decrease in the number of kisspeptin‐IR neurones after gonadectomy (GDX) combined with testosterone replacement in male rats .…”

“…Overgaard et al found that the number of kisspeptin‐IR cells in the ARC increased after gonadectomy in both male and female Wistar rats. They observed a decrease in the number of kisspeptin‐IR neurones after gonadectomy (GDX) combined with testosterone replacement in male rats . Gonadectomy with oestradiol replacement (GDX+E 2 ), however, induced no significant changes in the number of kisspeptin‐IR neurones.…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…51 Interestingly, data from the past few years suggest that the actual number of kisspeptin and/or NKB neurons might change during development. 52,53 Mutations in proteins that regulate ubiquitination such as OTU domain-containing protein 4 (encoded by OTUD4) and E3 ubiquitin-protein ligase RNF216 (also known as ring finger protein 216; encoded by RNF216), 54 as well as in proteins involved in lipid metabolism such as neuropathy target esterase (also known as patatin-like phospholipase domain-containing protein 6; encoded by PNPLA6) 55,56 have been identified in patients with Gordon Holmes syndrome (with associated CHH and ataxia). Thus, mutations in these three genes give rise to a broad and progressive neurodegenerative syndrome that includes CHH.…”

Analysis of gonadotrophin‐releasing hormone‐1 and kisspeptin neuronal systems in the nonphotoregulated seasonally breeding eastern rock elephant‐shrew (Elephantulus myurus)

“…This site has been found to contain more kisspeptin‐ir cell bodies in females than males during the breeding season in sheep (Cheng et al, ) and during the breeding and nonbreeding seasons in red deer (Barrell et al, ). Furthermore, in nonseasonally breeding mice, rats, and humans, there are more kisspeptin‐ir cell bodies and a greater density of kisspeptin‐ir processes in the arcuate/infundibular nucleus in females (Hrabovszky et al, ; Overgaard et al, ; Overgaard, Ruiz‐Pino, Castellano, Tena‐Sempere, & Mikkelsen, ). Interpretation of the sex difference in arcuate nucleus kisspeptin in the breeding season in the present study is confounded by the pregnant state of the females captured at that time.…”