Abstract
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.
Highlights
Ghrelin, a hormone produced in the stomach, is the most potent orexigenic hormone
A further study with this dose indicated that the effect of ICV liver-expressedantimicrobial peptide 2 (LEAP-2) (1.5 nmol/mouse) on food intake was mediated via the GHS-R1a since contrary to the LEAP-2-induced hypophagia, we failed to obtain any effect in GHS-R1a KO animals (Supplementary Figure S1B)
We first assessed the effect of LEAP-2 in fasting-induced food intake in rats and mice because fasting is associated with decreased leptin and increased ghrelin levels
Summary
A hormone produced in the stomach, is the most potent orexigenic hormone. Chronic ghrelin administration promotes weight gain and adiposity in rodents [1], as well as increasing voluntary food-intake in humans [2]. It was generally acknowledged that ghrelin is a multifaceted regulator of metabolism, meaning that ghrelin regulates energy balance in the short term by the induction of appetite and in the long term by the increase in adiposity [8,9]. Of note, these effects are associated with changes in glucose and/or lipid homeostasis [10,11,12]. It was shown that LEAP-2 was able to inhibit some of the main in vivo biological effects of ghrelin, such as hyperphagia, hyperglycemia and GH release in mice and rats [17]. Plasma LEAP-2/acyl-ghrelin ratio seems to be determinant to modulate GHS-R1a activity [19,20]
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