Kisspeptins and Precursor Protein

The KISS1 gene encodes prepro-kisspeptin, the 145 amino acid kisspeptin precursor. The cleavage products from prepro-kisspeptin are known as kisspeptins and these peptides of various lengths all include an Arg-Phe-NH2 motif at the carboxy-terminus. The decapeptide, kisspeptin-10, possesses the minimal peptide length to bind and activate KISS1R. The most abundant cleavage product is the 54 amino acid isoform known as kisspeptin-54 (KP54) or commonly referred to as kisspeptin. Less common isoforms include kisspeptin-14 (KP14), kisspeptin-13 (KP13) and kisspeptin-10 (KP10). In addition, the mammalian sequence of kisspeptin-54 is named kisspeptin1 where as another form occurs in non-mammalian organisms that is called kisspeptin2 (2).

Figure 2. Kisspeptins are formed by proteolytic cleavage of prepro-kisspeptin. Adapted from M.Tena-Sempere. GPR54 and kisspeptin in reproduction. Human Reproduction Update. 12(5), 631-639 (2006)

Regulation of the HPG Axis and Puberty

The KISS1 system plays a vital role in the regulation of reproduction and puberty. The system signals increased gonadotrophin secretion during puberty and establishes mammalian reproductive function and regulation of the hypothalamic-pituitary-gonadal (HPG) axis. By stimulating release of endogenous GnRH, kisspeptin stimulates the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the pituitary gland. In turn, this results in the release of sex steroids from the gonads. KISS1 expression increases abruptly at the time of puberty, which suggests that kisspeptin signaling is involved in triggering the onset of puberty. In addition, kisspeptin may contribute to generating preovulatory gonadotropin surge in females (4). Given that kisspeptin plays a key role in regulating reproduction, the kisspeptin signaling pathway is a therapeutic target in reproductive disorders.

Role in Metabolism

More recently, kisspeptin was shown to play a part in glucose homeostasis, locomotor activity and body weight control (4). A tri-hormonal regulatory circuit exists between pancreatic α-cells, hepatocytes and β-cells. Glucagon, produced by α-cells in the Islets of Langerhans, stimulates cAMP-PKA signaling. In turn, this signaling up-regulates transcription of the gluconeogenic gene program and of KISS1. This leads to increased production of glucose and hepatic glucose output, and to the production of kisspeptin1. Glucose stimulates insulin secretion, whereas kisspeptin1 inhibits insulin secretion from pancreatic β-cells (5). Regarding locomotor activity, research with Kiss1R KO (knock-out) mice has shown that in the absence of KISS1R signaling, locomotor activity is dramatically reduced and accompanied by reduction in food intake and energy expenditure. In addition, studies have shown that in the absence of KISS1R signaling, there is increased body weight and impairment of glucose homeostasis in female but not male mice (3).

Kisspeptin and Sexual Attraction

Kisspeptin was also found to enhance activity in parts of the human brain associated with love and sexual arousal. Olfactory and visual signals are central inputs involved in sexual attraction. A recent study demonstrated that kisspeptin enhances brain activity in response to olfactory and visual cues of attraction in healthy men. Due its link to attraction, researchers are investigating if kisspeptin therapeutics may have potential to treat psychosexual disorders in addition to common reproductive disorders (6).

Conclusion

The roles for kisspeptin are multi-faceted with involvement in cancer, reproduction, metabolism and attraction. Consequently, there is interest in developing kisspeptin agonists and antagonists as therapeutics for a range of conditions. To support life scientists and researchers studying kisspeptin, Bachem offers a selection of kisspeptin peptides in addition to a comprehensive custom synthesis services.

References

1) W.Dhillo. Timeline: Kisspeptins. Lancet Diabetes Endocrinol. 1(1), 12-13 (2013)

2) C.M.Tevisan et al. Kisspeptin/GPR54 system: What do we know about its role in human reproduction? Cell Physio. Biochem. 49, 1259-1276 (2018)

3) K.P.Tolson et al. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J. Clin. Invest. 124(7), 3075-3079 (2014)

4) M.A.Hussain et al. There is kisspeptin – and then there is kisspeptin. Trends Endocrinol. Metab. 26(10), 564-572 (2015)

5) W.Song et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell. Metab. 19(4), 667-681 (2014)

6) L.Yang et al. Kisspeptin enhances brain responses to olfactory and visual cues of attraction in men. JCI Insight. 5(3), e133633 (2020)