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.

Regulation of Pituitary Cocaine- and Amphetamine-Regulated Transcript Expression and Secretion by Hypothalamic Gonadotropin-Releasing Hormone in Chickens

“…In cows and ewes, CART is reported to be expressed in the ovary and present in ovarian follicular fluid (Kobayashi et al, 2004; Juengel et al, 2017). Moreover, in vitro experiments further supported that CART can inhibit basal and FSH-induced estradiol production in granulosa cells and may act as an important local autocrine/paracrine factor involved in the regulation of ovarian follicle development and steroidogenesis (Sen et al, 2007; Ma et al, 2016; Juengel et al, 2017). These pioneering findings, together with our convincing evidence showing that the expression and secretion of CART in chicken pituitary is regulated by GnRH (Figures 2–4), suggest that CART can act at different tier(s) of the hypothalamic-pituitary-gonadal axis (HPG) to regulate vertebrate reproduction (Kobayashi et al, 2004; True et al, 2013; Juengel et al, 2017).…”

“…CART peptide encoded by CART gene was first discovered in abundance in the rat hypothalamus, in which it may act as a downstream effector of leptin with potent appetite-suppressing activity (Douglass et al, 1995; Gautvik et al, 1996; Kristensen et al, 1998; Elias et al, 2001). Besides the hypothalamus, CART is also expressed in other brain regions, the peripheral nervous system (PNS) and peripheral tissues of mammals including the anterior pituitary, ovary, and pancreas (Koylu et al, 1997; Jensen et al, 1999; Thim et al, 1999; Murphy et al, 2000; Kobayashi et al, 2004; Wierup et al, 2006; Ma et al, 2016), and is suggested to be involved in the regulation of many other physiological processes, such as drug reward and reinforcement, stress, pancreatic secretion, bone remodeling, and ovarian follicle development and steroidogenesis (Kobayashi et al, 2004; Elefteriou et al, 2005; Sen et al, 2007; Rogge et al, 2008; Abels et al, 2016).…”

Dietary factors and serum antimüllerian hormone concentrations in late premenopausal women

“…(12) Others have also found that a high fat diet may increase follicular atresia. (11, 13, 15) However, a study in mice found no significant differences in serum AMH concentrations between those fed a low-fat or high-fat diet, suggesting that granulosa cell function may not be altered by high fat intake. (12) Studies of dietary fat and markers of ovarian reserve in humans are more limited.…”

Molecular Insight into the Interaction between Epigenetics and Leptin in Metabolic Disorders

“…Again, miRNAs related to leptin in fetal programming still remain a poorly studied area of research. Recently, Sinha et al studied a gestational diabetes murine model to investigate the epigenetic regulation of cocaine- and amphetamine-regulated transcript (CART), a gene which was previously found by this research group as a mediator of hyperleptinemia-induced infertility [132,133]. The whole set of combined epigenetic changes include (i) miRNAs, (ii) histone acetylation and methylation, and (iii) altered promoter methylation, switched on the CART promoter into hypersensitive to leptin during in utero fetal programming.…”