Estradiol modulates Kiss1 neuronal response to ghrelin

Am J Physiol Endocrinol Metab. 2014 Mar;306(6):E606-14. doi: 10.1152/ajpendo.00211.2013. Epub 2014 Jan 28.


Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-α (ERα) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the coexpression of GHSR mRNA and ERα selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX + E₂; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX + E₂ and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E₂ increase GHSR mRNA expression, modifying the colocalization rate with ERα and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E₂ alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology.

Keywords: growth hormone secretagogue receptor; hypothalamus; kisspeptin; metabolism; reproduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Animals
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Estradiol / blood
  • Estradiol / metabolism*
  • Estradiol / therapeutic use
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / metabolism
  • Estrogen Replacement Therapy
  • Female
  • Gene Expression Regulation / drug effects
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Kisspeptins / genetics
  • Kisspeptins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Ovariectomy / adverse effects
  • Rats
  • Receptors, Ghrelin / agonists*
  • Receptors, Ghrelin / genetics
  • Receptors, Ghrelin / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects


  • Estrogen Receptor alpha
  • Ghrelin
  • Kiss1 protein, mouse
  • Kisspeptins
  • Nerve Tissue Proteins
  • Receptors, Ghrelin
  • Recombinant Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Estradiol