PMID- 22508514
OWN - NLM
STAT- MEDLINE
DCOM- 20120814
LR  - 20240323
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 153
IP  - 6
DP  - 2012 Jun
TI  - Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen 
      suppression of gonadotropin secretion and body weight.
PG  - 2800-12
LID - 10.1210/en.2012-1045 [doi]
AB  - 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 alpha, 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 17beta-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 
      17beta-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.
FAU - Mittelman-Smith, Melinda A
AU  - Mittelman-Smith MA
AD  - Department of Pathology and the Evelyn F. McKnight Brain Institute, University of 
      Arizona College of Medicine, Tucson, Arizona 85724, USA.
FAU - Williams, Hemalini
AU  - Williams H
FAU - Krajewski-Hall, Sally J
AU  - Krajewski-Hall SJ
FAU - Lai, Josephine
AU  - Lai J
FAU - Ciofi, Philippe
AU  - Ciofi P
FAU - McMullen, Nathaniel T
AU  - McMullen NT
FAU - Rance, Naomi E
AU  - Rance NE
LA  - eng
GR  - R01 AG032315/AG/NIA NIH HHS/United States
GR  - U54 HD028934/HD/NICHD NIH HHS/United States
GR  - U54-HD28934/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120416
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Estrogens)
RN  - 0 (Gonadotropins)
RN  - 0 (Immunotoxins)
RN  - 0 (Kisspeptins)
RN  - 0 (Neuropeptide Y)
RN  - 0 (Ribosome Inactivating Proteins, Type 1)
RN  - 33515-09-2 (Gonadotropin-Releasing Hormone)
RN  - 4TI98Z838E (Estradiol)
RN  - 66796-54-1 (Pro-Opiomelanocortin)
RN  - 74913-18-1 (Dynorphins)
RN  - 86933-75-7 (Neurokinin B)
RN  - 9002-67-9 (Luteinizing Hormone)
RN  - 9002-68-0 (Follicle Stimulating Hormone)
RN  - EC 3.2.2.22 (Saporins)
SB  - IM
MH  - Animals
MH  - Arcuate Nucleus of Hypothalamus/cytology/drug effects/metabolism
MH  - Body Weight/drug effects/*physiology
MH  - Dynorphins/*metabolism
MH  - Estradiol/pharmacology
MH  - Estrogens/pharmacology
MH  - Female
MH  - Follicle Stimulating Hormone/blood/metabolism
MH  - Gonadotropin-Releasing Hormone/metabolism
MH  - Gonadotropins/blood/*metabolism
MH  - Immunohistochemistry
MH  - Immunotoxins/chemistry/pharmacology
MH  - Kisspeptins/*metabolism
MH  - Luteinizing Hormone/blood/metabolism
MH  - Neurokinin B/*metabolism
MH  - Neurons/drug effects/*metabolism
MH  - Neuropeptide Y/metabolism
MH  - Ovariectomy
MH  - Pro-Opiomelanocortin/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosome Inactivating Proteins, Type 1/chemistry
MH  - Saporins
PMC - PMC3359616
EDAT- 2012/04/18 06:00
MHDA- 2012/08/15 06:00
PMCR- 2013/06/01
CRDT- 2012/04/18 06:00
PHST- 2012/04/18 06:00 [entrez]
PHST- 2012/04/18 06:00 [pubmed]
PHST- 2012/08/15 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - en.2012-1045 [pii]
AID - EN-12-1045 [pii]
AID - 10.1210/en.2012-1045 [doi]
PST - ppublish
SO  - Endocrinology. 2012 Jun;153(6):2800-12. doi: 10.1210/en.2012-1045. Epub 2012 Apr 
      16.