Oxytocin Neurons Enable Melanocortin Regulation of Male Sexual Function in Mice


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.

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We would like to acknowledge the University of Toledo Advanced Microscopy & Imaging Center and the University of Virginia Ligand Assay and Analysis Core for the analysis of LH/FSH serum concentrations.


This work was supported by NIH award R01 HD081792 to JWH. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934.

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Correspondence to Jennifer W. Hill.

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Semple, E., Shalabi, F. & Hill, J.W. Oxytocin Neurons Enable Melanocortin Regulation of Male Sexual Function in Mice. Mol Neurobiol 56, 6310–6323 (2019). https://doi.org/10.1007/s12035-019-1514-5

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  • Paraventricular nucleus
  • Erectile dysfunction
  • Ejaculation
  • Melanocortin
  • Obesity
  • PVH
  • Hypothalamus
  • Oxytocin
  • Male
  • Mice
  • Sim1
  • Sim-1
  • MC4R
  • POMC