Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance

J Neuroendocrinol. 2011 Nov;23(11):1099-112. doi: 10.1111/j.1365-2826.2011.02144.x.


Low levels of the adipocyte hormone leptin are considered to be the key signal contributing to inhibited gonadotrophin-releasing hormone (GnRH) release and reproductive acyclicity during negative energy balance. Hypoleptinaemia-induced inhibition of GnRH may be initiated with upstream inhibition of the secretagogue kisspeptin (Kiss1) because GnRH neurones do not express leptin receptors. The present study aimed to determine whether eliminating the hypoleptinaemia associated with caloric restriction (CR), by restoring leptin to normal basal levels, could reverse the suppression of the reproductive neuroendocrine axis. Fifty percent CR resulted in significant suppression of anteroventral periventricular Kiss1 mRNA, arcuate nucleus (ARH) Kiss1 and neurokinin B (NKB) mRNA levels and serum luteinising hormone (LH). Restoring leptin to normal basal levels did not restore Kiss1 or NKB mRNA or LH levels. Surprisingly, leptin did not activate expression of phosphorylated signal-transducer and activator of transcription-3 in ARC Kiss1 neurones, indicating that these neurones may not relay leptin signalling to GnRH neurones. Previous work in fasting models showing restoration of LH used a pharmacological dose of leptin. Therefore, in a 48-h fast study, replacement of leptin to pharmacological levels was compared with replacement of leptin to normal basal levels. Maintaining leptin at normal basal levels during the fast did not prevent inhibition of LH. By contrast, pharmacological levels of leptin did maintain LH at control values. These results suggest that, although leptin may be a permissive signal for reproductive function, hypoleptinaemia is unlikely to be the critical signal responsible for ARC Kiss1 and LH inhibition during negative energy balance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caloric Restriction
  • Energy Metabolism*
  • Female
  • Hypothalamus / metabolism
  • Immunohistochemistry
  • Kisspeptins / genetics
  • Kisspeptins / metabolism*
  • Leptin / pharmacology
  • Leptin / physiology*
  • Luteinizing Hormone / blood
  • Luteinizing Hormone / metabolism*
  • RNA, Messenger / genetics
  • Radioimmunoassay
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction


  • Kisspeptins
  • Leptin
  • RNA, Messenger
  • Luteinizing Hormone