LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

Lu, Xuehan; Huang, Lili; Huang, Zhengxiang; Feng, Dandan; Clark, Richard J.; Chen, Chen

doi:10.3389/fendo.2021.717544

Cited by 29 publications

(17 citation statements)

References 73 publications

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“…Liver-expressed antimicrobial peptide 2 (LEAP2) is a 40-amino-acid peptide ( 1 ) identified as an endogenous antagonist ( 2 – 4 ) or inverse agonist ( 5 ) of the orexigenic hormone ghrelin’s receptor, growth hormone secretagogue receptor (GHSR) ( 6 , 7 ). LEAP2 is mainly expressed in the liver and jejunum and secreted into the blood circulation in a metabolic status-dependent way in rodents and humans ( 2 , 8 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

Involvement of POMC neurons in LEAP2 regulation of food intake and body weight

Chu

Peng

et al. 2022

Front. Endocrinol.

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Liver-expressed antimicrobial peptide 2 (LEAP2) is a newly discovered antagonist of the growth hormone secretagogue receptor (GHSR) and is considered the first endogenous peptide that can antagonize the metabolic actions of ghrelin. The effects of ghrelin administration on feeding behavior, body weight, and energy metabolism involve the activation of orexigenic neurons in the arcuate nucleus (ARC) of the hypothalamus. It is unclear, however, if LEAP2 applied directly to the ARC of the hypothalamus affects these metabolic processes. Here, we show that overexpression of LEAP2 in the ARC through adeno-associated virus (AAV) reduced food intake and body weight in wild-type (WT) mice fed chow and a high-fat diet (HFD) and improved metabolic disorders. LEAP2 overexpression in the ARC overrides both central and peripheral ghrelin action on a chow diet. Interestingly, this AAV-LEAP2 treatment increased proopiomelanocortin (POMC) expression while agouti-related peptide (AGRP)/neuropeptide Y (NPY) and GHSR levels remained unchanged in the hypothalamus. Additionally, intracerebroventricular (i.c.v.) administration of LEAP2 decreased food intake, increased POMC neuronal activity, and repeated LEAP2 administration to mice induced body weight loss. Using chemogenetic manipulations, we found that inhibition of POMC neurons abolished the anorexigenic effect of LEAP2. These results demonstrate that central delivery of LEAP2 leads to appetite-suppressing and body weight reduction, which might require activation of POMC neurons in the ARC.

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Section: Introductionmentioning

confidence: 99%

Involvement of POMC neurons in LEAP2 regulation of food intake and body weight

Chu

Peng

et al. 2022

Front. Endocrinol.

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“…Recently ( 16 , 17 ), liver expressed antimicrobial peptide 2 (LEAP2) was identified as an endogenous ligand of GHSR1a. LEAP2 was a secretory peptide first isolated from human blood in 2003 ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Serum levels of ghrelin and LEAP2 in patients with type 2 diabetes mellitus: correlation with circulating glucose and lipids

Xiong

et al. 2022

Endocrine Connections

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Objective: Ghrelin regulates body weight, food intake and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters. Design: A total of 16 females and 40 males, ages 23-68 years old normal (n = 27) and T2D patients (n = 29) were enrolled as a cross-sectional cohort. Results: Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and HbA1c in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose and HbA1c. Conclusions: This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing negative correlation with glucose and HbA1c.

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“…Recently, Md Nurul Islam et al demonstrated in a rat animal model that ghrelin and LEAP-2 cooperate to regulate feeding and energy homeostasis, and, similarly, results were obtained in observational research studies in humans [ 15 , 16 ]. Taking into consideration the findings from previous studies of LEAP-2 and ghrelin, rats have been extensively used as a model of pregnancy in similar studies to humans and could contribute to addressing specific physiological mechanisms because they share many biological features with humans.…”

Section: Introductionmentioning

confidence: 80%

Study of the Ghrelin/LEAP-2 Ratio in Humans and Rats during Different Phases of Pregnancy

Garcés

Buell-Acosta

Angel‐Müller

et al. 2022

IJMS

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The Liver-Expressed Antimicrobial Peptide 2 (LEAP-2) has emerged as an endogenous GHS-R antagonist and blunts the orexigenic action of ghrelin. This study aimed to determine the Ghrelin/LEAP-2 ratio in humans and rats during pregnancy. In humans, we conducted a nested case-control study within an observational prospective cohort. Healthy and mild preeclamptic pregnant women were studied at each trimester of gestation and three months postpartum. In addition, a group of non-pregnant women was studied into the follicular and luteal phases of the menstrual cycle. Furthermore, Ghrelin/LEAP-2 ratio was investigated in non-pregnant rats and at different periods of rat pregnancy. Human and rat serum ghrelin and LEAP-2 levels were determined using the commercially available ELISA kits. The Ghrelin/LEAP-2 ratio peak around the second trimester of gestation in healthy pregnant women (p < 0.05). Additionally, there were no statistically significant differences in Ghrelin/LEAP-2 ratio between healthy and preeclamptic pregnant women at each trimester of gestation (p > 0.05). The Ghrelin/LEAP-2 ratio in pregnant rat reached the peak around mid-gestation with a similar pattern to the human pregnancy. LEAP-2 was visualized by immunohistochemistry in human term placenta and rat placentas on days 12, 16 and 21 of pregnancy. In conclusion, this study provides the first evidence of a Ghrelin/LEAP-2 ratio peak around the half-way point of pregnancy onwards during human and rat pregnancy, and it might be associated with increased rates of weight gain during pregnancy. Thus, this study suggests that LEAP-2 and Ghrelin/LEAP-2 ratio might play an important role in maternal physiology adaptation of weight gain during pregnancy.

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LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

Cited by 29 publications

References 73 publications

Involvement of POMC neurons in LEAP2 regulation of food intake and body weight

Involvement of POMC neurons in LEAP2 regulation of food intake and body weight

Serum levels of ghrelin and LEAP2 in patients with type 2 diabetes mellitus: correlation with circulating glucose and lipids

Study of the Ghrelin/LEAP-2 Ratio in Humans and Rats during Different Phases of Pregnancy

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