The endogenous ghrelin antagonist, LEAP2, accelerates puberty onset in conditions of early obesity

Puberty is a key maturational process, highly dependent on energy resources. Ghrelin, a key orexigenic hormone that is increased during conditions of energy insufficiency, has been shown to partially inhibit puberty, acting via the growth hormone secretagogue receptor (GHSR). The hepatic peptide, LEAP2, has recently emerged as a potential GHSR antagonist involved in energy homeostasis, but its eventual function in pubertal regulation remains unexplored.

To investigate the role of LEAP2 in the control of pubertal maturation using an integral translational approach combining clinical data and preclinical models.

Circulating levels of LEAP2 were measured in prepubertal girls with obesity and in a preclinical model of overweight associated with advanced puberty. The impact of central acute and chronic administration of LEAP2 on various pubertal parameters was explored in female rats under distinct metabolic and hormonal conditions. The effects of LEAP2 on hypothalamic Kiss1 expression and Kiss1 neurons calcium activity were studied in rodent models.

Circulating LEAP2 levels were elevated in prepubertal girls with obesity and in a preclinical model of overweight associated with advanced puberty. Central injection of LEAP2 increased luteinizing hormone (LH) secretion in a dose-dependent manner in peripubertal female rats, either fed ad libitum or after 24-hour fasting, a condition known to elevate circulating ghrelin. Chronic central administration of LEAP2 in prepubertal female rats significantly advanced puberty onset; a phenomenon also observed in immature females subjected to 20% food restriction. The stimulatory effect of central LEAP2 on LH secretion was associated with increased hypothalamic Kiss1 expression. Analyses in brain slices from Kiss1-GCaMP mice showed that LEAP2 could attenuate ghrelin effects on calcium activity in RP3V and ARC Kiss1 neurons, which express Ghsr, supporting a modulatory effect at the level of the Kiss1 circuitry which drives GnRH release.

Our data provide the first evidence of the role of LEAP2 in the metabolic control of pubertal maturation, acting potentially via Kiss1 neurons.