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Mol. Hum. Reprod. Advance Access originally published online on November 23, 2004
Molecular Human Reproduction 2005 11(1):21-28; doi:10.1093/molehr/gah130
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Molecular Human Reproduction vol. 11 no. 1 © European Society of Human Reproduction and Embryology 2004; all rights reserved

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

M. Maccarrone1,6, E. Fride2, T. Bisogno3, M. Bari1, M.G. Cascio3, N. Battista1, A. Finazzi Agrò4, R. Suris2, R. Mechoulam5 and V. Di Marzo3,7

1Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy, 2Departments of Behavioral Sciences and of Molecular Biology, College of Judea and Samaria, 44837 Ariel, Israel, 3Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70, 80078 Pozzuoli (Napoli), 4Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy and 5Department of Natural Products, Hebrew University, 91120 Jerusalem, Israel

6 To whom correspondence should be addressed at: Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy. Email: maccarrone{at}vet.unite.it

7 To whom correspondence should be addressed at: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70, 80078 Pozzuoli (Napoli), Italy. Email: vdimarzo{at}icmib.na.cnr.it

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.

Key words: anandamide/2-arachidonoylglycerol/fertility/leptin/ob/ob mice


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