title: Leptin-Induced CART (Cocaine- and Amphetamine-Regulated Transcript) Is a Novel Intraovarian Mediator of Obesity-Related Infertility in Females.
abstract: Obesity is considered detrimental to women's reproductive health. Although most of the attention has been focused on the effects of obesity on hypothalamic function, studies suggest a multifactorial impact. In fact, obesity is associated with reduced fecundity even in women with regular cycles, indicating that there may be local ovarian effects modulating fertility. Here we describe a novel mechanism for leptin actions directly in the ovary that may account for some of the negative effects of obesity on ovarian function. We find that normal cycling, obese, hyperleptinemic mice fed with a high-fat diet are subfertile and ovulate fewer oocytes compared with animals fed with a normal diet. Importantly, we show that leptin induces expression of the neuropeptide cocaine- and amphetamine-regulated transcript (CART) in the granulosa cells (GCs) of ovarian follicles both in vitro and in vivo. CART then negatively affects intracellular cAMP levels, MAPK signaling, and aromatase mRNA expression, which leads to lower estradiol synthesis in GCs and altered ovarian folliculogenesis. Finally, in human samples from patients undergoing in vitro fertilization, we show a significant positive correlation between patient body mass index, CART mRNA expression in GCs, and CART peptide levels in follicular fluid. These observations suggest that, under obese conditions, CART acts as a local mediator of leptin in the ovary to cause ovarian dysfunction and reduced fertility.
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Emily
authors.initials: E
authors.lastname: Hayes
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Hen
authors.initials: H
authors.lastname: Prizant
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Srivastava
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hammes
authors.affiliation: Division of Endocrinology and Metabolism (X.M., E.H., H.P., S.R.H., A.S.), Department of Medicine, and Department of Obstetrics and Gynecology (R.K.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Aritro
authors.initials: A
authors.lastname: Sen
mesh_terms: D000328:Adult; D000818:Animals; D001141:Aromatase / Q000235:genetics*; D015153:Blotting, Western; D015992:Body Mass Index; D000242:Cyclic AMP / Q000378:metabolism; D059305:Diet, High-Fat; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D015571:Follicular Fluid / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D007247:Infertility, Female / Q000150:complications / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D020738:Leptin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D004958:Estradiol; D000242:Cyclic AMP; D001141:Aromatase