Arcuate Kisspeptin/Neurokinin B/Dynorphin (KNDy) Neurons Mediate the Estrogen Suppression of Gonadotropin Secretion and Body Weight

Abstract

Estrogen withdrawal increases gonadotropin secretion and body weight, but the critical cell populations mediating these effects are not well understood. Recent studies have focused on a subpopulation of hypothalamic arcuate neurons that coexpress estrogen receptor α, neurokinin 3 receptor (NK(3)R), kisspeptin, neurokinin B, and dynorphin for the regulation of reproduction. To investigate the function of kisspeptin/neurokinin B/dynorphin (KNDy) neurons, a novel method was developed to ablate these cells using a selective NK(3)R agonist conjugated to the ribosome-inactivating toxin, saporin (NK(3)-SAP). Stereotaxic injections of NK(3)-SAP in the arcuate nucleus ablated KNDy neurons, as demonstrated by the near-complete loss of NK(3)R, NKB, and kisspeptin-immunoreactive (ir) neurons and depletion of the majority of arcuate dynorphin-ir neurons. Selectivity was demonstrated by the preservation of proopiomelanocortin, neuropeptide Y, and GnRH-ir elements in the arcuate nucleus and median eminence. In control rats, ovariectomy (OVX) markedly increased serum LH, FSH, and body weight, and these parameters were subsequently decreased by treatment with 17β-estradiol. KNDy neuron ablation prevented the rise in serum LH after OVX and attenuated the rise in serum FSH. KNDy neuron ablation did not completely block the suppressive effects of E(2) on gonadotropin secretion, a finding consistent with redundant pathways for estrogen negative feedback. However, regardless of estrogen status, KNDy-ablated rats had lower levels of serum gonadotropins compared with controls. Surprisingly, KNDy neuron ablation prevented the dramatic effects of OVX and 17β-estradiol (E(2)) replacement on body weight and abdominal girth. These data provide evidence that arcuate KNDy neurons are essential for tonic gonadotropin secretion, the rise in LH after removal of E(2), and the E(2) modulation of body weight.

Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

“…Although the mechanism remains to be determined, these findings are relevant to understanding thermoregulatory dysfunction in menopausal women, who tolerate heat stress better after estrogen replacement therapy (52). We have previously shown that KNDy neurons are required for the rise in LH secretion after the removal of E 2 negative feedback (11). Fig.…”

“…Rats were also exposed to subneutral, neutral, and supraneutral T AMBIENT in an environmental chamber to determine if KNDy neuron ablation altered the ability to defend T CORE in response to environmental temperature challenges. Our previous studies have shown that KNDy neurons are required for tonic gonadotropin secretion, the rise in LH secretion after ovariectomy, and the E 2 modulation of body weight (11). Here we determine if KNDy neurons also participate in the E 2 modulation of thermoregulation.…”

“…All protocols were approved by the University of Arizona Animal Care and Use Committee and conformed to National Institutes of Health (Bethesda, MD) guidelines. The serum hormone levels, body weights, and the brain histology from rats used in the present study have been previously described (11). Please refer to ref.…”

“…Current evidence suggests that pulsatile GnRH secretion is modulated by a subpopulation of neurons in the arcuate (infundibular) nucleus that express estrogen receptor α (ERα), neurokinin 3 receptor (NK 3 R), kisspeptin, neurokinin B (NKB), and dynorphin (7)(8)(9)(10)(11). In the hypothalamus of postmenopausal women, these kisspeptin/NKB/ dynorphin (KNDy) neurons undergo an unusual somatic hypertrophy and express increased kisspeptin and NKB gene transcripts (12)(13)(14)(15).…”

“…The utility of NK 3 -SAP for selective ablation of KNDy neurons was recently documented (11). Circadian rhythms of T SKIN , T CORE , and activity were evaluated in KNDy-ablated and control rats that were OVX and then replaced with E 2 .…”