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  • In conclusion we show to our knowledge for

    2021-10-19

    In conclusion, we show, to our knowledge for D-Pantothenic acid sale the first-time, compelling evidence for functional OTR and GHSR crosstalk, which is likely via the formation of a novel OTR/GHSR heterocomplex with important downstream signalling consequences. This OTR/GHSR interaction is poised to play an important physiological role and it will be interesting to investigate this interaction further to confirm whether the observed crosstalk is indeed through the formation of a heterocomplex or through a more short-term dynamic interaction. In addition, investigations into the functionality of this interaction in future behavioural studies are now warranted, as these will lead to better understanding of disorders associated with downregulated OTR signalling. The findings from this study represent an intriguing potential for the development of novel therapeutics targeting central disorders involving oxytocinergic signalling, including appetite regulation, depression, schizophrenia and autism, and will subsequently lead to a better treatment efficacy compared to single GPCR targeted drugs with less associated side effects (Uhrig et al., 2016; Blevins et al., 2015; Mcquaid et al., 2014; Penagarikano et al., 2015).
    Author contributions
    Acknowledgments The study was funded by Science Foundation Ireland Research Centre Grant SFI/12/RC/2273 to the APC Microbiome Institute Ireland (to Timothy G Dinan, John F Cryan and Harriët Schellekens). The authors declare no conflicts of interest.
    Introduction Ghrelin is a 28-amino-acid peptide hormone produced by the stomach (Kojima and Kangawa, 2005) that plays critical roles in controlling growth hormone (GH) release and energy homeostasis. Active ghrelin is octanoylated at Ser3 (Gutierrez et al., 2008, Yang et al., 2008), and its actions are mediated through binding to the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor (GPCR) enriched in the pituitary gland and hypothalamus (Cruz and Smith, 2008). Upon ghrelin binding, GHSR is activated in pituitary D-Pantothenic acid sale and stimulates GH release (Kojima et al., 1999). The activation of GHSR in the hypothalamic arcuate nucleus stimulates appetite and promotes food intake (Cowley et al., 2003, Sun et al., 2004). Recent studies have indicated that an essential physiological role of ghrelin is to maintain viable blood glucose levels during chronic caloric restriction (CR) (Zhang et al., 2015, Zhao et al., 2010). During CR, maintaining sufficient blood glucose levels to enable brain function is critical to survival (Cahill, 2006). Ghrelin is secreted in response to CR and promotes survival by stimulating GH release, which functions to promote gluconeogenesis and maintains viable glucose levels (Li et al., 2012, Zhang et al., 2015). Under chronic CR, subtle changes in GH levels may determine whether blood glucose is maintained at a level consistent with survival. In such conditions, fine-tuning of ghrelin action is critical. Regulation of ghrelin production has been well studied—serum levels peak before meals and fall shortly afterward (Cummings et al., 2001, Nass et al., 2008). Some forms of bariatric surgery also reduce ghrelin levels (Cummings et al., 2002a). However, regulation of ghrelin action at the receptor level has not been described. Here, we report the discovery of a peptide hormone, liver-expressed antimicrobial peptide 2 (LEAP2), as an endogenous antagonist of the ghrelin receptor. We identified LEAP2 as a peptide with profound differentially regulated expression following bariatric surgery. The physiological role of LEAP2 has not been identified. In both gain- and loss-of-function experiments, we found that LEAP2 is a potent inhibitor of ghrelin action in vivo. Our findings reveal a hitherto-unknown mechanism regulating ghrelin action.
    Results
    Discussion Since the discovery of ghrelin, regulated secretion has been the sole mechanism described for controlling the action of this hormone. Our current studies reveal a hitherto-unknown mechanism of ghrelin regulation. We have discovered that LEAP2 is an intestinally derived regulatory hormone that acts as an endogenous antagonist of ghrelin action. LEAP2 inhibits ghrelin binding to GHSR in a noncompetitive manner (see Figure 1) and blocks ghrelin-mediated GH release and food intake (see Figure 2). Neutralizing LEAP2 with function-blocking antibodies enhanced ghrelin action in vivo (see Figure 3). Further, LEAP2 antagonizes the function of the ghrelin-GH axis in maintaining viability during chronic CR (see Figure 4). This discovery reveals a novel regulatory mechanism modulating ghrelin action; additionally, this study identifies LEAP2 as a potential therapeutic target for ghrelin-related diseases, including obesity and diabetes, anorexia, cachexia, alcohol abuse, and Prader-Willi Syndrome (Cummings et al., 2002b, Leggio et al., 2014, Müller et al., 2015).