ESPE Yearbook of Paediatric Endocrinology

Hum Mol Genet. 2020 Dec 18;29(20): 3443–3450.https://pubmed.ncbi.nlm.nih.gov/33089319/

The authors performed an experimental study in Kiss1 knock-out mice, followed by an observational study of patients with adrenal tumors. The findings indicate that KISS1/KISS1R signaling may be involved in obesity, metabolic disorders and even gonadal steroid hormone perturbations.

The kisspeptin receptor (KISS1R) and its physiological ligand, kisspeptin (KISS1), play an essential role in gonadotropin-releasing hormone (GnRH) secretion. Inactivating variants in the KISS1R gene are detected in patients with idiopathic hypogonadotropic hypogonadism (IHH) (1), while Kiss1r knockout (KO) mice (Kiss1r−/−) develop IHH, and similar to the human patients, respond to exogenous GnRH treatment (1). Furthermore, KO mice for the KISS1R ligand, kisspeptin (Kiss1−/−) develop a similar phenotype, confirming that KISS1 is the physiological ligand of KISS1R and that both molecules are required for GnRH release (2, 3). Recent studies have demonstrated that KISS1 is expressed widely in fetal adrenal cortex and that kisspeptin treatment induces dehydroepiandrosterone sulphate (DHEAS) secretion in a human adrenocortical carcinoma cell line and by human fetal adrenal cells (4).

First, the authors evaluated the adrenal pathology and secretion in Kiss1 KO mice. They found that Kiss1 deletion leads to persistence of the fetal X-zone in both male and female mice (as indicated by the continuing expression of the Akr1c18, Pik3c8, Inha and Cyp17a1 markers) and this was associated with hypersecretion of corticosterone and aldosterone. Although corticosterone concentrations normalized in older animals, hyperaldosteronism persisted. They then screened human patients with hypercortisolism or hyperaldosteronism caused by adrenal tumors. Interestingly, among the patients with steroid hormone hypersecretion, they identified one missense KISS1 and three KISS1R variants (two missense and one synonymous), which had all been previously described in patients with IHH or Kallmann syndrome.

These data suggest that KISS1 and/or KISS1R are involved in the adrenocortical development and hormonal secretion. In older adrenal cortex, in both humans and mice, hyperaldosteronism may be the consequence of KISS1/KISS1R deficiency, although stronger data are needed to conclude a causative effect. Finally, these data also indicate that KISS1/KISS1R signaling may be involved in obesity, metabolic disorders and even gonadal steroid hormone perturbations (i.e. in polycystic ovarian syndrome) in a sexually dimorphic manner, as seen in Kiss1−/− mice studied here.

Reference: 1. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003; 349(17): 1614–27.2. d’Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A. 2007; 104(25): 10714–9.3. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005; 102(5): 1761–6.4. Katugampola H, King PJ, Chatterjee S, Meso M, Duncan AJ, Achermann JC, Guasti L, Ghataore L, Taylor NF, Allen R, Marlene S, Aquilina J, Abbara A, Jaysena CN, Dhillo WS, Dunkel L, Sankilampi U, Storr HL. Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit. J Clin Endocrinol Metab. 2017; 102(9): 3349–3359.