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  • Ghrelin is a brain gut peptide hormone secreted from the

    2022-06-22

    Ghrelin is a brain-gut peptide hormone secreted from the stomach to stimulate food intake by acting on its receptor, growth hormone secretagogue receptor (GHSR). GHSR is expressed throughout the brain and in NPY/AgRP neurons in the ARC (Cowley et al., 2003, Willesen et al., 1999). Ghrelin-expressing neurons are also found in the periventricular region of the hypothalamus dorsal to the ARC (Guan et al., 2003, Mondal et al., 2005). ARC and peripheral ghrelin administration induces NPY/AgRP gene expression (Chen et al., 2004, Goto et al., 2006, Kamegai et al., 2001, Kamegai et al., 2000), NPY activation (Wang et al., 2002), and potently depolarizes NPY neurons (Andrews et al., 2008, Cowley et al., 2003). Furthermore, ghrelin activation of GHSR potently excites NPY neurons and controls calcium homeostasis (Andrews et al., 2008, Cowley et al., 2003). These rapid effects of ghrelin potentially involve calcium channels (Kohno et al., 2003) and may involve the inhibition of the M-current as recently reported in striatal neurons (Shi et al., 2013). Activation of GHSR in NPY neurons initiates a signaling cascade that involves the mitochondrial enzymes uncoupling protein 2 (UCP2) and carnitine palmitoyltransferase 1 (CPT-1) to control Npy/Agrp gene expression through a forkhead box O1 (FoxO1)-mediated mechanism (Andrews, 2011, Andrews et al., 2008, López et al., 2008a). CPT-1 is involved in malonyl-CoA sensing and fatty Protease Inhibitor Cocktail (EDTA-Free, 200X in DMSO) oxidation, while UCP2 is necessary for reactive oxidation species (ROS) buffering and mitochondrial biogenesis (Andrews, 2011, López et al., 2008b). Of the three types of CPT-1, hypothalamic neurons express CPT-1c, which does not have acyltransferase activity, while hypothalamic astrocytes express CPT-1a, which does have acyltransferase activity (Wolfgang et al., 2006). FoxO1 is a transcription factor that negatively regulates adipogenesis, mediates insulin-induced gluconeogenesis, and is an effector of Npy/Agrp gene expression (Cao et al., 2011, Ren et al., 2012). Fasting and diet-induced obesity (DIO) regulate expression of Npy, Agrp, Ghsr, and Ucp2 in the ARC (Briggs et al., 2014, Briggs et al., 2013, Briggs et al., 2010, Coppola et al., 2007, Verhulst et al., 2012), which may be a contributing mechanism underlying the ghrelin resistance seen in DIO (Briggs et al., 2014, Briggs et al., 2010, Perreault et al., 2004). Furthermore, a high fat diet (HFD) or DIO inhibits ghrelin's augmentation of hyperphagia (Gardiner et al., 2010, Perez-Tilve et al., 2011). Recently, E2 was shown to increase Ghsr expression in the ARC (Frazao et al., 2014). Interestingly, E2 is an anorexigenic steroid and is known to induce Pomc and suppress Npy gene expression (Roepke, 2009). Because ghrelin is orexigenic, this E2-induced increase in Ghsr expression in the ARC may be independent of its effects on feeding and occur in other ARC neurons. Because GHSR and the components of its signaling pathway are widely expressed in the heterogeneous cell types of the ARC, determinations of gene expression only in the ARC may lead to incorrect assumptions about their modulation in NPY neurons. Therefore, our hypothesis is that there will be significant differences in gene expression between the ARC and NPY neurons due to fasting and DIO. We also hypothesize that there will be distinct sex differences in the response to these dietary influences due, in part, to E2 in females. To address these hypotheses, we characterized the expression of Ghsr, Ucp2, Cpt1c, Foxo1, and Npy/Agrp in both the ARC and NPY neurons in males after fasting and DIO and in ovariectomized females with or without E2 replacement after fasting and DIO using wild type (WT) C57 mice and GFP-NPY transgenic mice.
    Materials & methods
    Results
    Discussion We showed that fasting and DIO have opposing effects on Npy/Agrp and Ghsr expression in the ARC that is recapitulated in pools of NPY neurons from male mice. However, two genes involved in GHSR signaling, Ucp2 and Foxo1, were differentially regulated in between the ARC and NPY neurons in fasted males. EB replacement in fed, ovx females increased Agrp, Ghsr, Cpt1c, and Foxo1 in the ARC but only Agrp in pools of NPY neurons. In fasted females, EB replacement also increased Ghsr, Cpt1c, and Foxo1 expression in the ARC but only Foxo1 in NPY pools. In ovx, ND-fed females, EB replacement augmented Agrp, which was abrogated by HFD in both the ARC and NPY pools; however, regulation of Ghsr expression by EB was not affected by HFD in the ARC nor did EB increase Ghsr expression in NPY pools. Therefore, our data suggest that fasting, HFD (DIO), and E2 have differential effects on GHSR signaling between the heterogeneous ARC and homogenous pools of NPY neurons in a sex-specific manner. A summary of the differential regulation of GHSR signaling molecules is presented in Table 2.