Sexual Dimorphism in Kisspeptin Signaling

Abstract

Kisspeptin (KP) and kisspeptin receptor (KPR) are essential for the onset of puberty, development of gonads, and maintenance of gonadal function in both males and females. Hypothalamic KPs and KPR display a high degree of sexual dimorphism in expression and function. KPs act on KPR in gonadotropin releasing hormone (GnRH) neurons and induce distinct patterns of GnRH secretion in males and females. GnRH acts on the anterior pituitary to secrete gonadotropins, which are required for steroidogenesis and gametogenesis in testes and ovaries. Gonadal steroid hormones in turn regulate the KP neurons. Gonadal hormones inhibit the KP neurons within the arcuate nucleus and generate pulsatile GnRH mediated gonadotropin (GPN) secretion in both sexes. However, the numbers of KP neurons in the anteroventral periventricular nucleus and preoptic area are greater in females, which release a large amount of KPs in response to a high estrogen level and induce the preovulatory GPN surge. In addition to the hypothalamus, KPs and KPR are also expressed in various extrahypothalamic tissues including the liver, pancreas, fat, and gonads. There is a remarkable difference in circulating KP levels between males and females. An increased level of KPs in females can be linked to increased numbers of KP neurons in female hypothalamus and more KP production in the ovaries and adipose tissues. Although the sexually dimorphic features are well characterized for hypothalamic KPs, very little is known about the extrahypothalamic KPs. This review article summarizes current knowledge regarding the sexual dimorphism in hypothalamic as well as extrahypothalamic KP and KPR system in primates and rodents.

Keywords: GnRH neurons; extrahypothalamic kisspeptins; gonadotropins; kisspeptin neurons; kisspeptins; sexual dimorphism.

Figure 3

Estrogen feedback regulation of kisspeptin neurons in the arcuate and anteroventral periventricular nuclei. While estrogen negatively regulates the kisspeptin (KP) neurons in the arcuate (ARC) nuclei, positively regulates those in the anteroventral periventricular (AVPV) nuclei. ERα-mediated estrogen signaling in the KP neurons of ARC nuclei induces the pulsatile gonadotropin secretion during the estrus cycle. In addition, estrogen signaling in the KP neurons of AVPV nuclei induces preovulatory gonadotropin surge in proestrus evening. +ve, positive; −ve, negative.

Figure 1

Expression and processing of pre-pro-kisspeptin. Kisspeptins (KPs) are encoded as a common precursor. The pre-pro-kisspeptin is a 145 amino acid peptide, with a 19-amino acid signal peptide and a main 54-amino acid region (52 amino acid in in rodents), kisspeptin-54/52 (KP-54/52). KP-54/52 is further processed into peptides of lower molecular weight: KP-14, KP13, and KP-10. All KPs contain the RF-amide (in primates) or RG-amide (in rodents) motif in the C-terminus that can bind and activate the KP receptor.

Figure 2

Circulating kisspeptin levels in men and women. Kisspeptins (KPs) are detected in the human plasma. Sex specific events, such as neonatal testosterone surge in males and pregnancy in females, can affect the plasma KP levels. KP levels also change with increasing age but exhibit significant sexual dimorphism after puberty. In both men and women, the highest KP levels are detected during puberty and thereafter, plasma KP levels decrease with aging.

Figure 4

Kisspeptin expression in arcuate nuclei. The changes in kisspeptin (KP) expression in females (black line) and males (green line) were traced through the neonatal/prepubertal periods, the pubertal period, and the adulthood in previous studies. There is a high degree of sexual dimorphism in KP expression in the arcuate (ARC) nuclei during neonatal and prepubertal period. The sex-specific dimorphic expression of KPs in ARC nuclei sustains until the onset of puberty when the levels of KP expression become similar.

Figure 5

Kisspeptin expression in anteroventral periventricular and preoptic nuclei. The changes in kisspeptin (KP) expression in females (black line) and males (green line) were traced through the neonatal/prepubertal periods, the pubertal period, and the adulthood in previous studies. Until the second postnatal week, the expression of KP in the anteroventral periventricular and periventricular preoptic nucleus (AVPV/PeN) was not detectable. After KP expression becomes detectable in this region, a distinct sexual dimorphism persists throughout the postnatal life.

Figure 6

Sexual dimorphism in hypothalamic kisspeptins. Kisspeptin (KP) neurons are located in two major regions: the arcuate (ARC) nuclei, and the anteroventral periventricular and periventricular preoptic nuclei (AVPV/PEN). KPR are expressed on the GnRH neurons. KPs expressed in hypothalamic nuclei are crucial for the onset of puberty, gonadal development, and maintenance of reproductive functions. Sex-specific differences in the numbers of KP neurons and the KP expression levels exist in the hypothalamus. KP neurons in ARC nuclei generate pulsatile GnRH secretion, while those in the AVPV nuclei induce the preovulatory gonadotropin surge (thick line). GnRH neurons, found near the pituitary gland, is innervated by the KP neurons of ARC and AVPV origins. While the KP expression in the ARC nuclei is similar between males and females, KP expression is highly dimorphic in the AVPV nuclei due to greater numbers of KP neurons in females. Thin lines stand for lower levels and thick lines stand for higher levels of expression.

Figure 7

Neonatal testosterone surge in males. In the males, there is a transient increase of testosterone level soon after the birth. This event, also known as “mini-puberty” is driven by male-specific neonatal kisspeptin (KP) neurons and results in the activation of the hypothalamic-pituitary axis. There is no parallel phenomenon in the females. This neonatal testosterone surge (NTS) is critical for the establishment sexual dimorphism in the AVPV/ PeN nuclei depleting the KP neurons in males. The NTS is also important for the normal development of male reproductive system.

Figure 8

Hypothalamic and extrahypothalamic expression of kisspeptins and kisspeptin receptor in the brain. Anatomical distribution of kisspeptin (KP) mRNA (green dots) and KP receptor (KPR) mRNA (brown dots) in different brain areas of rodents. KP mRNA expression is mostly detected in the hypothalamus (ARC, AVPV, and PeN). Presence of KP mRNAs has also been reported in the amygdala (AMY) and bed nucleus of stria terminalis (BST). KPR mRNA has been detected in different forebrain areas, including the diagonal band of Broca (DBB), and septum (S).

Figure 9

Extrahypothalamic kisspeptin and kisspeptin receptor in gonads. Kisspeptins (KPs) and KP receptor (KPR) are expressed in the sperm. KPs are not detected in spermatids but KPR is expressed in acrosomal region of spermatids and mature spermatozoa. KPs and KPR are also detected in the ovaries. While KPs are predominantly expressed by the granulosa cells, KPR is expressed in the oocytes. KPR+ve, stands for kisspeptin receptor positive.

Figure 10

Role of kisspeptin signaling in metabolism. Kisspeptins (KP) and KP receptor (KPR) are present in liver, pancreas, fat, and gonad tissues. KPR^KO male mice suffered from with feeding suppression and decreased body weight. They had increased adiposity but did not develop glucose intolerance. In contrast, KPR^KO female mice gained bodyweight, higher leptin levels, marked adiposity with impaired glucose intolerance. The findings in KPR^KO mice suggest that KP-signaling impacts energy expenditure, food intake and body weight gain in a sexually dimorphic manner.