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Altered Kisspeptin Responsiveness in Bmal1 Knockout Females
Author(s) -
Tonsfeldt Karen J,
Schoeller Erica,
Brusman Liza,
Mellon Pamela
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.989.7
Subject(s) - kisspeptin , endocrinology , medicine , ovulation , luteinizing hormone , knockout mouse , hypothalamus , gonadotropin releasing hormone , neuropeptide , biology , chemistry , hormone , receptor
The use of the hypothalamic peptide kisspeptin is a novel treatment for hypothalamic infertility. The preovulatory luteinizing hormone (LH) surge occurs in the hypothalamic‐pituitary‐gonadal axis to initiate ovulation. Estrogen primes kisspeptin (Kiss1) neurons in the anteroventral periventricular nucleus (AVPV) to secrete kisspeptin, which potently activates gonadotropin‐releasing hormone (GnRH) neurons to release a pulse of GnRH, eliciting a surge of LH to prompt ovulation. A critical component of this preovulatory surge is temporal gating. Knockout of Bmal1 ‐ a critical component of the molecular circadian clock ‐ produces arrhythmic and infertile animals. Female Bmal1 KOs show no detectable LH surge but normal pituitary responsiveness, suggesting hypothalamic dysfunction. Our study sought to characterize neuroendocrine function in these mice, particularly responsiveness to kisspeptin. Corroborating previous studies, we found no difference in the LH response to 1 μg/kg GnRH 10 minutes after administration between wildtype (WT) and Bmal1 KOs (LH increase of 2.61 ± 0.25 ng/μl vs 2.51 ± 0.50 ng/μl, n=6). Interestingly, Bmal1 KO female mice had a significantly increased response to 30 nmole kisspeptin after 10 minutes (LH increase of 1.19 ± 0.34 ng/μl vs. 3.08 ± 0.56 ng/μl, n = 6, p<0.05). In addition to having an increased LH response to a kisspeptin challenge, the knockout mice showed greater area under the curve in response to kisspeptin during a 45‐minute time course (38.99 ± 4.69 vs 163.30 ± 16.88 ng/min/μl, n=3–4, p<0.005). A dose response curve indicated no difference in ED 50 (0.144 ± 0.048 vs. 0.085 ± 0.048 mg/kg, n=4) despite the increased maximal effect, suggesting kisspeptin is more efficacious in eliciting LH in Bmal1 knockout females. Since the sex‐specific expression of Kiss1 in the AVPV is critical for regulating ovulation in females, we hypothesized that this population may be absent in Bmal1 KO females. However, we found no differences in Kiss1 mRNA expression between WT and Bmal1 KO females (1.08 ± 0.25 vs 1.03±0.29‐fold change, n=4). Overall, our results suggest disruption of the hypothalamic and pituitary regulation of fertility in the Bmal1 KO females, specifically in responsiveness to kisspeptin. Our findings suggest that circadian cues are important for regulating the temporal release of hypothalamic peptides that regulate fertility, and these findings may help direct kisspeptin treatment in women with circadian‐derived hypothalamic amenorrhea. Support or Funding Information NIH R01 HD072754, R01 HD082567, P50 HD012303, T32 HD007203