Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight

Melinda A. Mittelman-Smith, Hemalini Williams, Sally J. Krajewski-Hall, Josephine Lai, Philippe Ciofi, Nathaniel T. McMullen, Naomi E. Rance

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Estrogen withdrawal increases gonadotropin secretion and body weight, but the critical cell populations mediating these effects are not well understood. Recent studies have focusedona subpopulation of hypothalamic arcuate neurons that coexpress estrogen receptor α, neurokinin 3 receptor (NK 3R), kisspeptin,neurokininB,anddynorphinfortheregulation of reproduction.Toinvestigatethefunction of kisspeptin/neurokinin B/dynorphin (KNDy) neurons, a novel method was developed to ablate these cells using a selective NK 3R 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 3R, 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. KN Dyneuron 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.

Original languageEnglish (US)
Pages (from-to)2800-2812
Number of pages13
JournalEndocrinology
Volume153
Issue number6
DOIs
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Endocrinology

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