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  • Though regulation of ghrelin interaction with

    2022-05-18

    Though regulation of ghrelin interaction with GHSR has not been described previously, a precedent for a similar regulatory mechanism exists in the form of the interaction between Agouti-Related Protein (AgRP) and melanocortin receptor subtypes MC3R and MC4R (Ollmann, 1997). AgRP is produced by hypothalamic PD153035 hydrochloride and acts as an inverse agonist of MC3R and MC4R. AgRP stimulates food intake by antagonizing the satiety-promoting activity of these receptors (Barsh and Schwartz, 2002). Such endogenous counter-regulatory mechanisms may be more widespread than previously appreciated, as exemplified by the role we describe here for LEAP2. Previous studies indicated that at high concentrations (>6.6 μM), LEAP2 exhibits antimicrobial activity in vitro (Howard et al., 2010, Krause et al., 2003). The effective antimicrobial concentration reported in these studies is much higher than the physiological levels of LEAP2 (∼2 nM) (Figure S3H). In our current study, we found that physiological levels of LEAP2 antagonize GHSR (IC50 = 6.0 nM; Figure 1G). Relatively small fluctuations in LEAP2 levels have a dramatic impact on ghrelin biology, as a 3-fold increase of LEAP2 concentration significantly exacerbated survival during chronic CR (Figure 4). Thus, our current discovery identifies a role for LEAP2 that occurs at physiological levels of the hormone. Another notable finding is that LEAP2 may suppress ghrelin action through additional mechanisms beyond inhibiting ghrelin binding with GHSR. An inverse relationship is found between circulating levels of LEAP2 and ghrelin in response to changes in nutritional status. After a fast, serum LEAP2 decreased while serum ghrelin increased, whereas upon refeeding, serum LEAP2 increased while serum ghrelin decreased (Figure S3H). After chronic CR, ghrelin levels increased less in LEAP2-expressing mice as compared to the control group (see Figures 4E and S4G). We speculate that LEAP2 may therefore also act to inhibit the production or secretion of ghrelin. This dual mechanism of inhibition (antagonizing the ghrelin receptor and inhibiting ghrelin production) makes LEAP2 a particularly strong regulator of ghrelin actions in vivo and may explain how small fluctuations in LEAP2 can exert a powerful effect on ghrelin biology. Determining whether GHSR-independent actions of LEAP2 contribute to these dual regulatory mechanisms will be a fruitful area for future study. For example, evaluating the action of LEAP2 in GHSR-knockout mice could help to determine whether LEAP2’s regulation of ghrelin production occurs through GHSR antagonism or a distinct mechanism. Our discovery adds LEAP2 to the list of hormones that connect the gut, brain, and metabolic control. Leap2 expression in the stomach is nearly undetectable under normal physiological conditions but is dramatically increased following VSG surgery (see Figures 1B and 1C). This increase of LEAP2 may contribute to appetite suppression following bariatric surgery. Elucidation of the neuroendocrine changes that occur following the profound metabolic remodeling of bariatric surgeries is revealing molecular mechanisms that link the gastrointestinal tract with metabolic control (Seeley et al., 2015). Harnessing these mechanisms may provide new and less invasive therapeutic strategies for treating neuroendocrinological and metabolic diseases.
    STAR★Methods
    Author Contributions
    Acknowledgments
    Introduction Ghrelin is a 28-amino acid peptide that binds to the G protein-coupled receptor (GPCR) growth hormone secretagogue receptor 1a (GHSR) to induce a release of growth hormone (Kojima et al., 1999). Ghrelin is best characterized as an orexigenic peptide, as increased levels stimulate hunger via GHSR activation (Cummings et al., 2001). GHSR has high constitutive activity (Holst et al., 2004) and dynamism in the apo state (Schrottke et al., 2017). Mutational work has examined the structural basis for this basal activity (Goze et al., 2010, Holst et al., 2010, Valentin-Hansen et al., 2012) and identified ligand binding sites (Els et al., 2012, Holst et al., 2004, Holst et al., 2006, Holst et al., 2007, Holst et al., 2009, Liu et al., 2007, Mokrosinski et al., 2012). However, the majority of this work has focused on small-molecule ligands, while binding of the endogenous peptide remains unknown.