Circulating LEAP-2 is associated with puberty in girls

Barja-Fernández, Silvia; Lugilde, Javier; Castelao, Cecilia; Vázquez-Cobela, Rocío; Seoane, Luísa M.; Diéguez, Carlos; Leis, Rosaura; Tovar, Sulay

doi:10.1038/s41366-020-00703-3

Cited by 21 publications

(17 citation statements)

References 50 publications

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“…Barja-Fernandez et al. revealed a positive correlation between plasma LEAP2 and HOMA-IR in children [ 15 ]. In girls, plasma LEAP2 also was positively correlated with body weight, Tanner stage, lean mass, and plasma triglycerides, while in boys, plasma LEAP2 showed a correlation with fat mass and blood glucose [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…revealed a positive correlation between plasma LEAP2 and HOMA-IR in children [ 15 ]. In girls, plasma LEAP2 also was positively correlated with body weight, Tanner stage, lean mass, and plasma triglycerides, while in boys, plasma LEAP2 showed a correlation with fat mass and blood glucose [ 15 ]. Additionally, plasma LEAP2 was positively correlated with % fat mass in pubertal children but not in prepubertal children [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

Shankar

Metzger

Singh

et al. 2021

Molecular Metabolism

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Objective The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. Methods We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. Results LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2–119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O 2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. Conclusions LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

Shankar

Metzger

Singh

et al. 2021

Molecular Metabolism

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“…As hyperandrogenism is the major endocrine disorder of PCOS patients, it is reasonable to suspect that androgen may suppress LEAP-2 independent of ghrelin. A cross-sectional study of 150 children between 3- and 17-year-old revealed that girls showed a higher LEAP-2 level than boys, here LEAP-2 level was independent of BMI, whereas ghrelin did not show this gender dimorphism ( 64 ). In addition, LEAP-2 was significantly higher in pubertal than prepubertal girls, while ghrelin level was higher in prepubertal children than pubescents regardless of gender ( 64 ).…”

Section: Association Between Leap-2 and Obese-related Diseasesmentioning

confidence: 99%

“…A cross-sectional study of 150 children between 3- and 17-year-old revealed that girls showed a higher LEAP-2 level than boys, here LEAP-2 level was independent of BMI, whereas ghrelin did not show this gender dimorphism ( 64 ). In addition, LEAP-2 was significantly higher in pubertal than prepubertal girls, while ghrelin level was higher in prepubertal children than pubescents regardless of gender ( 64 ). Thus, sex hormones are likely to play a role in regulating LEAP-2.…”

Section: Association Between Leap-2 and Obese-related Diseasesmentioning

confidence: 99%

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

Huang

et al. 2021

Front. Endocrinol.

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Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.

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Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner

Andreoli,

Fittipaldi,

Castrogiovanni

et al. 2023

Eur J Nutr

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Circulating LEAP-2 is associated with puberty in girls

Cited by 21 publications

References 50 publications

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

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

Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner

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