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  • 84 9 More recently it was discovered that

    2020-10-08

    More recently, it was discovered that BChE hydrolyzes the neuropeptide gut hormone, ghrelin [25], [26], [27], [28]. Nonetheless, because the enzyme reaction is very slow, those who first reported this finding were initially reluctant to attribute a real physiological role for that phenomenon. Our own views changed when we accidentally linked high level gene transfer of BChE in group-housed male mice to reduced stress, reduced aggression and reduced levels of plasma ghrelin [29]. We are now confident that ghrelin modulation represents an important physiological role for this enzyme and, in light of that role, there is real potential for using BChE to modulate ghrelin’s impact in many types of emotional disorders. Ghrelin is a 28-amino 84 9 peptide with a serine residue acylated by octanoic acid. This feature is essential for binding and activating its primary target, the G-protein-coupled growth hormone secretagogue receptor (GSHR) [30], [31]. The major source of plasma ghrelin derives from endocrine cells in the stomach, which release it into the general circulation. Circulating ghrelin then feeds back on the stomach to stimulate gastric muscles that produce “hunger pangs.” It triggers afferent vagal neurons in the stomach to activate CNS regions involved in food seeking. At the same time plasma ghrelin also penetrates the blood brain barrier to stimulate GHSR and drive food cravings. In addition, brain neurons in or near the pituitary gland and hypothalamus produce and release ghrelin locally. Activating GHSR in the pituitary leads to growth hormone secretion, while activation elsewhere plays a role in many other processes including glucose homeostasis and fat storage [32], [33]. Because BChE is present in both the bloodstream and the brain, its hydrolytic activity plays a role in regulating ghrelin signaling by cleaving its acyl group to form desacyl-ghrelin, which is the dominant form of the peptide in plasma and CSF [34]. Therefore, changes in blood BChE activity, e.g., in response to an anticholinesterase (anti-ChE), can shift the balance of GHSR signaling in favor of active acyl-ghrelin. However, desacyl-ghrelin also has multiple effects in a GHSR-independent manner. These relationships further highlight the physiological implications of altering ghrelin metabolism by reducing BChE activity with enzyme inhibitors or raising it with BChE gene transfer [29], [35], [36], [37]. Ghrelin serves as a stimulant for hedonic feeding, promoting food intake and fat storage [38], [39], [40]. Healthy lean individuals experience a drive for food in response to ghrelin pulses [38]. Circulating ghrelin levels are influenced by food intake, being high before a meal and low afterwards [41]. The most obvious role for BChE’s modulation of ghrelin is to regulate feeding behavior/food intake. Under ordinary conditions, circulating BChE is stable, with little change from hour to hour, day to day, or week to week. In contrast, levels of ghrelin released by the stomach or within the brain can change sharply across time. If BChE levels are too low, the drive to eat could be heightened. It has been reported that obese humans and dogs have modestly higher plasma BChE and lower plasma ghrelin than their lean counterparts [42], [43]. Similar findings have been reported in mouse models of obesity [44]. By the same token, when obese humans and mice succeed in recovering their original healthy weight, plasma BChE falls and plasma ghrelin rises, often markedly. Evidence to date thus suggests that the levels of BChE activity and ghrelin activity are inversely coupled. This implies a potential for changes in plasma or tissue BChE to influence ghrelin metabolism and thereby impact the respective signaling pathways of acyl- and desacyl-ghrelin [45]. Following up these insights it seems feasible to manipulate BChE levels to impact ghrelin-driven overeating and obesity [46].
    Cholinesterases and pharmacological effects of inhibitors in the periphery