Abstract
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.
Highlights
Food intake is one of the most deceptively complex of all mammalian behaviours, being regulated by a variety of homeostatic and external factors [1]
Ghrelin or ghrelin ligands can access the brain from the periphery by circumventing the blood brain barrier (BBB) at permeable locations adjacent to homeostatic appetite centres, and indirectly influence reward centres through neural connections stemming from these areas [74,384]
The importance of GHSR-1a signalling in the mesolimbic dopaminergic pathway as a barometer for the incentive salience of food has been well described
Summary
Food intake is one of the most deceptively complex of all mammalian behaviours, being regulated by a variety of homeostatic and external factors [1]. One of the key hormones regulating food intake is ghrelin, a 28 amino acid (aa) peptide synthesized and secreted by gastric oxyntic cells [2]. Blood levels of this hormone exhibit circadian fluctuation which are aligned with mealtimes, spiking pre-prandially followed by rapid post-prandial reductions [3]. All of the above has led to the designation of ghrelin as the “hunger hormone” [3], recent findings provide evidence for compensatory mechanisms in ghrelin knockouts [4] To date it remains the only known peripheral hormone with orexigenic effects via a centrally mediated mechanism [5,6,7]. Ghrelin has been shown to be involved in reward processes, mood, memory and learning, and stress response [17,18,19], while peripheral functions span gastric motility, glucose homeostasis, immune function, cardiac output and bone formation [20,21,22,23,24,25]
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