Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1

Abstract

Purpose: The objective of this study was to test the hypothesis that ovarian kisspeptin (kiss1) and its receptor (kiss1r) expression are affected by age, obesity, and the age- and obesity-related chemokine monocyte chemoattractant protein-1 (MCP-1).

Methods: Ovaries from reproductive-aged and older C57BL/6J mice fed normal chow (NC) or high-fat (HF) diet, ovaries from age-matched young MCP-1 knockout and young control mice on NC, and finally, cumulus and mural granulosa cells (GCs) from women who underwent in vitro fertilization (IVF) were collected. Kiss1, kiss1r, anti-Mullerian hormone (AMH), and AMH receptor (AMHR-II) messenger RNA (mRNA) expression levels were quantified using real-time polymerase chain reaction (RT-PCR).

Results: In mouse ovaries, kiss1 and kiss1r mRNA levels were significantly higher in old compared to reproductive-aged mice, and diet-induced obesity did not alter kiss1 or kiss1r mRNA levels. Compared to young control mice, young MCP-1 knockout mice had significantly lower ovarian kiss1 mRNA but significantly higher AMH and AMHR-II mRNA levels. In human cumulus GCs, kiss1r mRNA levels were positively correlated with age but not with BMI. There was no expression of kiss1 mRNA in either cumulus or mural GCs.

Conclusion: These data suggest a possible age-related physiologic role for the kisspeptinergic system in ovarian physiology. Additionally, the inflammatory MCP-1 may be associated with kiss1 and AMH genes, which are important in ovulation and folliculogenesis, respectively.

Keywords: Aging; Kisspeptin; MCP-1; Obesity; Ovary.

Fig. 1

Weight gain following high-fat (HF) diet. Mice on HF diet (n = 6) gained significantly more weight than mice on normal chow diet (n = 6) after a 12-week feeding period. Baseline represents 6-week-old mice. *p < 0.05

Fig. 2

Ovarian kiss1 and kiss1r expression in relatively reproductive-aged and older mice. Six mice on normal chow or six mice on high-fat diet had oophorectomy at 20 weeks (reproductive-aged group). The remaining six mice in the NC group continued NC while the remaining six on HF diet were converted to NC and both groups had oophorectomy at 32 weeks (older group) of age. Kiss1 and kiss1r mRNA expression levels were significantly higher in older (n = 10) compared to reproductive-aged mice (n = 8). Diet-induced weight gain did not affect kiss1 or kiss1r mRNA expression levels. *p < 0.05

Fig. 3

Ovarian kiss1, kiss1r, AMH, and AMHR-II mRNA expression levels in young MCP-1 knockout and young wild-type mice. Young MCP-1 knockout mice and young C57BL/6J wild-type female mice had oophorectomy at 6 weeks of age. Compared to wild-type mice (n = 5), MCP-1 KO mice (n = 6) had significantly lower ovarian kiss1 mRNA expression levels (p = 0.01) but significantly higher AMH (p = 0.02) and AMHR-II mRNA expression levels (p = 0.0007). *p < 0.05

Fig. 4

Correlation between age and kiss1r mRNA expression levels in cumulus granulosa cells (GCs) collected from women who underwent in vitro fertilization. Cumulus GCs were collected by mechanically cutting the cumulus cell layer from each oocyte following oocyte retrieval. Kiss1r mRNA levels were positively correlated with age

Fig. 5

Stratification by age of kiss1r mRNA expression levels in cumulus granulosa cells (GCs) collected from women who underwent in vitro fertilization. Cumulus GCs were collected by mechanically cutting the cumulus cell layer from each oocyte following oocyte retrieval. Women aged 35 (n = 4) had significantly lower kiss1r mRNA expression level compared to women aged between 35 and 39 (n = 6) who had significantly lower kiss1r mRNA expression levels compared to women aged ≥ 40 (n = 2). Data are described as median (range). a p < 0.05 compared to <35; b p < 0.05 compared to 35–39