Oxytocin Neurons Enable Melanocortin Regulation of Male Sexual Function in Mice

Mol Neurobiol. 2019 Sep;56(9):6310-6323. doi: 10.1007/s12035-019-1514-5. Epub 2019 Feb 12.


The melanocortin pathway has been implicated in both metabolism and sexual function. When the melanocortin 4 receptor (MC4R) is knocked out globally, male mice display obesity, low sexual desire, and copulatory difficulties; however, it is unclear whether these phenotypes are interdependent. To elucidate the neuronal circuitry involved in sexual dysfunction in MC4R knockouts, we re-expressed the MC4R in these mice exclusively on Sim1 neurons (tbMC4RSim1 mice) or on a subset of Sim1 neurons, namely oxytocin neurons (tbMC4Roxt mice). The groups were matched at young ages to control for the effects of obesity. Interestingly, young MC4R null mice had no deficits in sexual motivation or erectile function. However, MC4R null mice were found to have an increased latency to reach ejaculation compared to control mice, which was restored in both tbMC4RSim1 and tbMC4Roxt mice. These results indicate that melanocortin signaling via the MC4R on oxytocin neurons is important for normal ejaculation independent of the male's metabolic health.

Keywords: Ejaculation; Erectile dysfunction; Hypothalamus; MC4R; Male; Melanocortin; Mice; Obesity; Oxytocin; POMC; PVH; Paraventricular nucleus; Sim-1; Sim1.

MeSH terms

  • Animals
  • Female
  • Gonadal Steroid Hormones / metabolism
  • Green Fluorescent Proteins / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism*
  • Oxytocin / metabolism*
  • Receptor, Melanocortin, Type 4 / metabolism*
  • Sexual Behavior, Animal*


  • Gonadal Steroid Hormones
  • Receptor, Melanocortin, Type 4
  • Green Fluorescent Proteins
  • Oxytocin