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Circulating LEAP-2 is associated with puberty in girls



Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese.

Methods and results

Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels.


This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

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Fig. 1: LEAP-2 circulating levels in the study population.
Fig. 2: Ghrelin circulating levels in the study population.


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This work has been supported by grants from Ministerio de Economía y Competitividad (ST: BFU2016-79208-R; CD: BFU2014-55871) Xunta de Galicia (ST: ED431F 2016/013 and RYC-2014-15811), Instituto de Salud Carlos III (PI11/02059 and PI16/01301) Xunta de Galicia: Centro singular de investigación de Galicia accreditation 2019-2022 and the European Union: European Regional Development Fund – ERDF (ED431G 2019/02). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The authors would like to thank the children and the parents who participated in the study.

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SBF, JL, LMS, RL, CD, and ST made contributions to conception and design. SBF, JL, and RVC contributed to acquisition of the data. SBF, LMS, RL, CD, and ST contributed to the analysis and interpretation of the data. LMS, CD, and ST critically revised the manuscript for important intellectual content. SBF, JL, LMS, RL, CD, and ST gave final approval of the version to be published. ST and CD formulated the hypothesis, secured the funding, coordinated the project, and wrote the manuscript. ST is responsible for the integrity of the work as a whole.

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Correspondence to Rosaura Leis or Sulay Tovar.

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Barja-Fernández, S., Lugilde, J., Castelao, C. et al. Circulating LEAP-2 is associated with puberty in girls. Int J Obes 45, 502–514 (2021).

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