Substantiation of Ovarian Effects of Leptin by Challenging a Mouse Model of Obesity/ Type 2 Diabetes P. Pallares a, * , R.A. Garcia-Fernandez b , L.M. Criado c , C.A. Letelier a,d , J.M. Fernandez-Toro c , D. Esteban c , J.M. Flores b , A. Gonzalez-Bulnes a a Departamento de Reproduccion Animal, INIA, Avda, Puerta de Hierro s/n. 28040-Madrid, Spain b Departamento de Medicina y Cirugia Animal, Facultad de Veterinaria, UCM, 28040-Madrid, Spain c Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). Melchor Fernandez Almagro 3. 28029-Madrid, Spain d Instituto de Ciencia Animal y Tecnologia de Carnes, UACh. Casilla 567, Valdivia, Chile Received 24 August 2009; received in revised form 5 January 2010; accepted 9 January 2010 Abstract The goal of the current was to elucidate if treatment with gonadotrophins and leptin can circumvent infertility in obese mice and to establish whether reproductive effects of leptin are influenced at the hypothalamus-hypophysis or ovarian level by using a leptin deficient mouse model of obesity/type 2 diabetes (ob/ob) treated with leptin. The ovulatory response and the fertilization success were compared with the results obtained in ob/ob dams pretreated with a gonadotrophin-replacement therapy or in two groups (ob/ ob and wild-type) of control non-pretreated females. The number of corpora lutea was significantly lower in control ob/ob mice than in wild-type dams. Treatment with gonadotrophin-replacement therapy did not increase significantly the ovulation rate in ob/ob, but the administration of leptin-replacement treatment allowed the authors to obtain a number of corpora lutea and oocytes/zygotes similar to those obtained in wild-type females. Furthermore, the leptin supply succeeded in producing fertilized zygotes, although in a lower number than found in the wild-type control. Thus, the hypogonadotrophic state in obese mice may be circumvented by the administration of a gonadotrophin-replacement therapy combined with a protocol for controlled ovarian stimulation, but fertile ovulations are only obtained after applying leptin-replacement therapy. Current results strongly support the existence of direct local effects of leptin on the ovary. # 2010 Elsevier Inc. All rights reserved. Keywords: Folliculogenesis; Gonadotrophins; Leptin; Mouse; Ovary 1. Introduction The changes in circulating levels of glucose and metabolic hormones (insulin, growth hormone, IGF-I and leptin) are thought to be important signaling factors for the female reproductive system as increases in these elements positively correlate with follicle development and ovulation [1]. Several studies that take into consideration the influence of leptin on glucose and insulin homeostasis [2,3] have lead to the hypothesis that this polypeptide has a major role in the regulation of the reproductive function via nutritional contribution [4,5]. Furthermore, blood leptin concentrations vary with changes in nutrition and are correlated with body fatness [6,7], since leptin is produced in the adipose tissue [8]. The obese mouse hereditable syndrome was initially discovered in 1949 [9]; however, leptin was not www.theriojournal.com Available online at www.sciencedirect.com Theriogenology 73 (2010) 1088–1095 * Corresponding author. Tel.: +34 91 347 4030; fax: +34 91 347 40 14. E-mail address: pallares.pilar@inia.es (P. Pallares). 0093-691X/$ – see front matter # 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.theriogenology.2010.01.008