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    • br Introduction Ghrelin is a amino acid peptide

    2021-09-11


    Introduction Ghrelin is a 28-amino Bestatin hydrochloride mg peptide mainly produced in the stomach and small intestines with the kidneys, placenta, and pancreas contributing to miniscule amounts of circuiting ghrelin [1]. Ghrelin exists in circulation in two major forms: acyl ghrelin (AG) and desacyl ghrelin (DAG). During posttranslational processing, proghrelin is coupled with an octanoic acid at the serine-3 residue by the membrane-bound enzyme, ghrelin O-acyltransferase (GOAT), to form AG [2], [3]. This fatty acid modification is entirely unique to ghrelin and is required for the optimal binding of ghrelin to its receptor, the growth hormone secretagogue receptor (GHSR) 1a [4], [5], which is a 7-transmembrane G-protein coupled receptor widely expressed in body tissues but with the highest expression in the CNS (i.e. pituitary gland) [5], [6]. AG acts peripherally and centrally to regulate biological functions including stimulating growth hormone secretion, promoting positive energy balance and food reward, regulating glucose metabolism, and enhancing gut motility [7]. DAG is the predominant form of ghrelin, but the lack of acylation precludes it from binding to GHSR 1a and subsequent receptor activation [1], [8]. Despite this, many biological functions have been ascribed to DAG, including the protective effect of cortical neuronal injury, regulation of glucose and lipid metabolism, food intake, and stress behavior [9], [10], [11], [12], [13], [14]. We have shown previously that ghrelin also enhances sniffing and olfactory sensitivity, two important functions for food seeking, by acting directly on the olfactory bulb [15]. It has been long recognized that in the brain, particularly in the hypothalamus, ghrelin plays a key role in the homeostatic regulation of energy and glucose metabolism [10], [16], [17]. Additionally, ghrelin may modulate reward neurocircuits and memory by acting in areas of the brain behind an intact blood–brain barrier (BBB) [7]. Nutrients and signals from the gut, pancreas, and adipose tissue are transported to the central nervous system (CNS) by crossing the BBB or the blood-cerebrospinal fluid (CSF) barrier [18], [19]. To cross the vascular BBB, substances must cross the restrictive brain endothelium and then traverse astrocyte endfeet before reaching brain interstitium [20]. We and others have shown that the BBB plays a direct role in mediating communication between the brain and the gastrointestinal (GI) tract by controlling the transfer of peptides and regulatory proteins between blood and CNS [21]. Not only can the GI tract secrete substances that affect CNS function [22], [23], but GI hormones can modulate brain endothelial cells and alter their ability to secret substances into the CNS affecting behavior or function [24], [25]. An example of such gut-brain communication is the orexigenic effect of ghrelin. The stomach derived hormone works centrally by activating the neuropeptide Y/agouti-related protein (NPY/AgRP) neurons and inhibiting the pro-opiomelanocortin (POMC) neurons in the hypothalamus to promote a positive energy balance [26], [27], [28]. We previously studied the ability of human AG (hAG), mouse AG (mAG), and mouse DAG (mDAG) to cross the BBB of the mouse brain in the brain-to-blood and blood-to-brain directions and found that AG (mouse and human) crosses the BBB in a bidirectional and saturable manner, but mDAG only travels from blood to brain unidirectionally and in an unsaturable manner [29]. These paradoxical findings suggest that the transport efficiency of ghrelin may be related to the n-octanoyl side chain. The objective of the current research is to investigate whether AG transport across the BBB is GHSR dependent by using the Ghsr null mouse model. In addition, since the transport of human DAG (hDAG) across the BBB has not been previously characterized, we wanted to test its BBB transport properties to determine if hDAG transport is more efficient than hAG or mDAG. Given the known central action of ghrelin to regulate food intake and food reward, we also examined brain regional transport of ghrelin to see if the pattern correlates with its known functions.