The study aims to delineate the effects of the naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP-2) on postprandial glucose metabolism and food intake in obese volunteers. The overall objective is to investigate the physiological importance of LEAP-2 in obese subjects.

开始日期2022-08-24

申办/合作机构-

NCT04897984 / Completed早期临床1期IIT

The Kinetics of LEAP2 in Man

The study aims to investigate the kinetics of the naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP-2) in healthy volunteers. The overall objective is to investigate the physiological importance of LEAP-2 in healthy subjects.

开始日期2021-05-24

申办/合作机构

Gentofte Hospital

NCT04621409 / Completed早期临床1期IIT

Effects of LEAP-2 on Postprandial Glucose Metabolism and Food Intake

The study aim to delineate the effects of the naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP-2) on postprandial glucose metabolism and food intake in healthy volunteers. The overall objective is to investigate the physiological importance of LEAP-2 in healthy subjects.

开始日期2020-11-17

申办/合作机构

Gentofte Hospital

100 项与 GHSR x LEAP2 相关的临床结果

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100 项与 GHSR x LEAP2 相关的转化医学

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0 项与 GHSR x LEAP2 相关的专利（医药）

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项与 GHSR x LEAP2 相关的文献（医药）

2024-09-26·Endocrinology

The LEAP2 Response to Cancer-Related Anorexia-Cachexia Syndrome in Male Mice and Patients

Article

作者: Garcia, Jose M ; Ogden, Sean B ; Singh, Omprakash ; Kerr, Haiming L ; Mani, Bharath K ; Osborne-Lawrence, Sherri ; Paul, Subhojit ; Gupta, Deepali ; Metzger, Nathan P ; Anderson, Lindsey J ; Lawrence, Connor ; Zigman, Jeffrey M ; Richard, Corine P ; Shankar, Kripa ; Piñon, Francisco ; Varshney, Salil

AbstractThe hormone ghrelin serves a protective role in cancer-related anorexia-cachexia syndrome (CACS)—a condition in which plasma levels of ghrelin rise, its administration lessens CACS severity, and experimentally reduced signaling by its receptor (GHSR) worsens fat loss and anorexia and accelerates death. Yet, actions for the related hormone liver-expressed antimicrobial peptide-2 (LEAP2), which is an endogenous GHSR antagonist, are unexplored in CACS. Here, we found that plasma LEAP2 and LEAP2/ghrelin ratio were lower in Lewis lung carcinoma (LLC) and RM-9 prostate cancer CACS mouse models. Ghrelin deletion exaggerated losses of tumor-free body weight and fat mass, reduced food intake, reduced soleus muscle weight, and/or lowered grip strength in LLC or RM-9 tumor-bearing mice. LEAP2 deletion lessened reductions in tumor-free body weight and fat mass and increased food intake in LLC or RM-9 tumor-bearing mice. In a 55-subject cohort of patients with CACS or weight-stable cancer, the plasma LEAP2/total ghrelin ratio was negatively correlated with 6-month weight change preceding blood collection. These data demonstrate that ghrelin deletion exacerbates CACS in the LLC and RM-9 tumor-bearing mouse models while contrastingly, LEAP2 deletion reduces measures of CACS in these tumor-bearing mouse models. Further, they suggest that lower plasma LEAP2/ghrelin ratio protects against worsened CACS.

2024-09-18·Journal of Endocrinology

The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner

Article

作者: Sarkar, Debalina ; King, Aileen J F ; Gilon, Patrick ; Delishaj, Blerinda ; Dereli, Ayse S ; Patterson, Michael ; Bolton, Olivia ; Despontin, Chloe ; Hewawasam, Nirun ; Reeves, Sue ; Hauge-Evans, Astrid C ; Almutairi, Maha

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts the effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here, we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell-type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (P < 0.01) but not females (P > 0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (P < 0.001) but not females (P > 0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4, and Sstr3 islet mRNA expression did not differ between sexes, whereas the SSTR3 antagonist MK4256 enhanced glucose-induced insulin secretion in islets from males only. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (P < 0.05), with a trend towards reversal by LEAP2 (P = 0.06). Both were abolished by 72 h E2 pre-treatment (10 nmol/L, P > 0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (P < 0.001) but not E2-treated islets (P > 0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P < 0.05) and Ghsr1a upregulated (P < 0.0001) in islets from Sst−/− mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

2024-09-01·Heliyon

Deficiency of leap2 promotes somatic growth in zebrafish: Involvement of the growth hormone system

Article

作者: Li, Xi ; Shan, Yunfeng ; Ye, Minjie ; Guan, Kaiyu ; Chen, Xiaoyu ; Guo, Anqi

PurposeLiver-expressed antimicrobial peptide-2 (LEAP2) is identified as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor type 1a (GHSR1a), its effect on the GHSR1a is contrary to the role of GHRELIN. Growth hormone (GH) is a crucial hormone for early development. Previous studies report that LEAP2 dose-dependently attenuates ghrelin-induced GH secretion, and Leap2-knockout mice exhibit increased plasma GH levels after GHRELIN administration. Clinical data revealed a possible correlation between LEAP2 and height development. However, the role of LEAP2 in early development remains unclear. This study aimed to investigate the role of LEAP2 in early development using leap2 mutant zebrafish larvae as a model.MethodWe analyzed the conservation of LEAP2 peptide across multiple species and generated leap2 mutants in zebrafish by CRISPR-Cas9, dynamically observed and measured the growth and development of zebrafish larvae from fertilization to 5 day post fertilization (dpf). In situ hybridization, transcriptome sequencing, quantitative real-time PCR and Western blot were used to detect the expression levels of GH and its signaling in early stage of embryonic development.ResultOur data demonstrate that zebrafish with a knockout of the leap2 gene display a significant increase in hatching rate, body length, and the distance between their eyes, all without visible developmental defects in the early stages of development. In addition, both RNA and protein analyses revealed a significant increase in GH expression in leap2 mutant.ConclusionIn general, this study demonstrates that LEAP2 regulates the expression of GH during early development, particularly influencing body length.