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  • GHSR A s have high levels

    2021-10-23

    GHSR-1A's have high levels of constitutive activity and recent investigations show that constitutively active GHSR-1As in the absence of ligand (ghrelin) binding can have effects on feeding and energy balance (Mear et al., 2013, Petersen et al., 2009). Furthermore, GHSR-1As are capable of dimerizing with other feeding-relevant receptor types (e.g. Type-1 dopamine receptors and melanocortin-3 receptors) (Jiang et al., 2006, Rediger et al., 2011, Wellman and Abizaid, 2015). Thus, there is the possibility that vHP GHSR-1A mediated STFP might be regulated by GHSR-1A constitutive activity and/or signaling mechanisms relating to GHSR-1A dimerization as opposed to peripheral ghrelin secretion and eventual binding to vHP GHSR-1As. In light of this, we examined the requirement of peripheral ghrelin circulation on the expression of STFP by reducing peripheral ghrelin levels with l-cysteine (McGavigan et al., 2015, Sirohi et al., 2017). In the current study, our results demonstrated that IP administration of l-cysteine prior to social interaction impairs STFP and reduces circulating total and active ghrelin levels without impacting active GLP-1 levels, suggesting that peripheral ghrelin secretion and central ghrelin ligand binding is necessary for GHSR-1A-mediated effects on learned social feeding behaviors. Consistent with this possibility, work from Diano et al. (2006) has demonstrated that peripherally secreted ghrelin is capable of entering the hippocampal formation, where it binds to hippocampal neurons and facilitates synapse formation and long-term potentiation (Diano et al., 2006). Previous research has demonstrated that meal-entrained rats, who learn to anticipate meals based on circadian cues, show elevated preprandial circulating ghrelin levels. This is in 3X FLAG tag Peptide mg to similarly food-deprived, freely-fed rats who do not show this preprandial rise in ghrelin levels (Drazen et al., 2006). Moreover, data from our lab has shown that vHP ghrelin receptor blockade in meal-entrained rats exhibit a reduction in meal size during the entrainment period, suggesting that the vHP is a site of action for the integration of circulating ghrelin with learned feeding behaviors (Hsu et al., 2015). Given these data, it is possible that in addition to circadian cues, peripheral circulating ghrelin might exhibit a pre-prandial rise in response to not only social food cues, but also in response to other types of learned food-related cues (e.g. environmental food cues), that in turn allow an animal to anticipate future meals. This hypothesis however, requires further examination. Overall, these data provide evidence for a neurobiological mechanism for learned, social-related feeding behaviors whereby ghrelin secretion from the stomach traverses to the central nervous system and engages GHSR-1As within the vHP to facilitate the acquisition and/or consolidation of mnemonic associations between social cues and food intake. While the results from the l-cysteine experiment suggest that vHP GHSR-1A-mediated STFP enhancement requires ghrelin-GHSR-1A ligand-receptor binding, the current study did not directly examine the relative contribution of GHSR-1A constitutive activity vs. peripheral ghrelin circulation on learned, social feeding behaviors. Future studies should utilize a combination of inverse agonists for GHSR-1As to silence constitutive activity [e.g., [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P (Holst et al., 2003)] as a selective means to reduce peripheral ghrelin secretion to determine the relative impact of these mechanisms on learned feeding behaviors. It is also important to note that while l-cysteine is a potent means of reducing circulating ghrelin levels, the mechanisms through which l-cysteine reduces peripheral ghrelin levels are currently unknown. Moreover, peripheral l-cysteine administration has been shown to influence central serotonin levels (Invernizzi et al., 1989) and has neuroprotective effects (Liu et al., 2017) via yet unknown pathways, and therefore it is possible that STFP deficits were based on nonspecific actions of l-cysteine. Further investigations involving learned feeding behaviors and inhibition of ghrelin producing P/D1 stomach cells or halting acylation of ghrelin into its active form (e.g. via ghrelin-o-acetyltransferase inhibitors, see (Barnett et al., 2010, Teuffel et al., 2015, Wellman et al., 2015)) would complement the present l-cysteine data.