Up-regulation of the endocannabinoid system in the uterus of leptin knockout (ob/ob) mice and implications for fertility

M. Maccarrone*, E. Fride, T. Bisogno, M. Bari, M. G. Cascio, N. Battista, A. Finazzi Agrò, R. Suris, R. Mechoulam, V. Di Marzo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)


The levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) are under the negative control of leptin in the rodent hypothalamus. As leptin and endocannabinoids play opposite roles in the control of reproduction, we have investigated whether the impaired fertility typical of leptin-defective ob/ob mice is due, in part, to enhanced uterine endocannabinoid levels. We found that levels of both anandamide and 2-AG in the uterus of ob/ob mice are significantly elevated with respect to wild-type littermates, due to reduced hydrolase activity in the case of anandamide, and to reduced monoacylglycerol lipase and enhanced diacylglycerol lipase activity in the case of 2-AG. Furthermore, the process mediating endocannabinoid cellular uptake was also impaired in ob/ob mice, whereas the levels of cannabinoid and anandamide receptors were not modified. Although ineffective in wild-type mice, treatment of ob/ob mice with leptin re-established endocannabinoid levels and enzyme activities back to the values observed in wild-type littermates. Finally, treatment of ob/ob females with the CB1 receptor antagonist SR141716A did not improve their fertility, and inhibition of endocannabinoid inactivation with the endocannabinoid uptake inhibitor OMDM-1 in wild-type females did not result in impaired fertility.

Original languageEnglish
Pages (from-to)21-28
Number of pages8
JournalMolecular Human Reproduction
Issue number1
Publication statusPublished - 1 Jan 2005

Bibliographical note

Funding Information:
We wish to thank Drs Filomena Fezza, Valeria Gasperi and Cinzia Mazzei (University of Rome ‘Tor Vergata’) for their valuable help in biochemical assays. This study was partly supported by the Ministero dell’Istruzione, dell’Università e della Ricerca (COFIN 2003 to M.M.), Rome.


  • 2-Arachidonoylglycerol
  • Anandamide
  • Fertility
  • Leptin
  • Ob/ob mice


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