“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Gupta, Deepali; Ogden, Sean B.; Shankar, Kripa; Varshney, Salil; Zigman, Jeffrey M.

doi:10.1016/j.molmet.2020.101128

Cited by 33 publications

(28 citation statements)

References 191 publications

(198 reference statements)

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“…Consistent with this, mice lacking LEAP-2 displayed enhanced ghrelin-induced feeding and GH release [18]. Thus, plasma LEAP-2/acyl-ghrelin ratio seems to be determinant to modulate GHS-R1a activity [19,20].…”

Section: Introductionsupporting

confidence: 59%

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner

Lugilde

Casado

Beiroa

et al. 2022

Cells

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Data gleaned recently shows that ghrelin, a stomach derived peptide, and liver-expressed-antimicrobial peptide 2 (LEAP-2) play opposite roles on food intake. However, the data available with LEAP-2 in relation to in vivo studies are still very scanty and some key questions regarding the interplay among ghrelin and LEAP-2 remain to be answered. In this work, using rats and mice, we study fasting-induced food intake as well as testing the effect of diet exposure, e.g., standard diet and high fat diet, in terms of ghrelin-induced food intake. The anorexigenic effect of LEAP-2 on fasting induced food intake appears to be dependent on energy stores, being more evident in ob/ob than in wild type mice and also in animals exposed to high fat diet. On the other hand, LEAP-2 administration markedly inhibited ghrelin-induced food intake in lean, obese (ob/ob and DIO) mice, aged rats and GH-deficient dwarf rats. In contrast, the inhibitory effect on glucose levels can only be observed in some specific experimental models indicating that the mechanisms involved are likely to be quite different. Taken together from these data, LEAP-2 emerged as a potential candidate to be therapeutically useful in obesity.

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Section: Introductionsupporting

confidence: 59%

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner

Lugilde

Casado

Beiroa

et al. 2022

Cells

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“…It is produced and secreted mainly by X/A oxyntic mucosa endocrine cells of the stomach [18,19]. Two major forms of ghrelin were found in the circulation: unacylated ghrelin, which is the main circulating form, and acyl-ghrelin, which is the active form generated by otanoylation of the serine at position 3, a process mediated by ghrelin O-acyl transferase (GOAT) [20,21]. This acylation is essential for binding to the GHSR-1a and for most already known endocrine actions of ghrelin.…”

Section: Physiology Of the Gh/igf-1 Axismentioning

confidence: 99%

Contribution of Ghrelin to the Pathogenesis of Growth Hormone Deficiency

Lewiński

Karbownik-Lewińska

Wieczorek-Szukała

et al. 2021

IJMS

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In this review we described the interactions between ghrelin and the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in children and adults with growth hormone deficiency (GHD). A possible involvement of these interactions in the pathogenesis of unexplained cases of GHD was suggested. Current research provides more and more details to the knowledge on the circadian rhythm of ghrelin. We gathered reports on the decreasing effect of Helicobacter pylori-related chronic gastritis on the number of ghrelin immunopositive cells and the consequent decrease in ghrelin serum concentration. The gastrointestinal tract microflora modification of the ghrelin action, by the mechanism of molecular mimicry, was also stressed. Moreover, the mutual relationships between ghrelin and the TSH-FT4/FT3 axis in growth and metabolic processes are described. It is to be recalled that FT4 and FT3 exert a permissive impact on IGF-1 action and, in turn, GH, in reaction mediated by IGF-1, enhances the monodeiodination of FT4 to FT3. Finally, we discussed the latest attempts to use the GH secretagogue receptor (GHS-R) analogues for possible diagnostic and therapeutic purposes.

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“…Setting aside the findings in the latter four studies, the aforementioned data led to the hypothesis that LEAP2 might offset the actions of acyl-ghrelin and contribute to the state of ghrelin resistance associated with obesity [ [20] , [21] , [22] , [23] ]. For example, acyl-ghrelin fails to acutely induce food intake in diet-induced obese mice and in obese Agouti mice whether acutely or chronically administered [ [24] , [25] , [26] ].…”

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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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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“A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes”

Cited by 33 publications

References 191 publications

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner

Contribution of Ghrelin to the Pathogenesis of Growth Hormone Deficiency

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

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