Physiological Effect of Ghrelin on Body Systems

Abstract

Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.

Figure 1

The structure of ghrelin. Ghrelin is a 28-amino-acid peptide with an n-octanoyl group attached to serine at position 3 that is critical for the majority of its activity.

Figure 2

Study Selection process using PRISMA.

Figure 3

Physiological effect of ghrelin. ACTH: adrenocorticotropic hormone; IGF-1: insulin-like growth factor-1; BP: blood pressure. Up/down arrows denote increase/decrease.

Figure 4

Transport of h-ghrelin, m-ghrelin, and des-m-ghrelin across the BBB of mice. Although octanoylated (bioactive) m-ghrelin crosses the mouse BBB predominantly in the brain-to-blood direction, passage for des-m-ghrelin was observed only in the blood-to-brain direction. H-ghrelin, which differs from m-ghrelin in two amino residues only, was transported in both directions in mice. The extent to which and the direction in which the ghrelin can cross the BBB are therefore influenced by at least two features of its primary structure, its posttranslationally added fatty acid side chain and its amino acid sequence.

Figure 5

Effect of ghrelin on two main brain regions: arcuate nucleus (ARC) of the hypothalamus and the ventral tegmental area (VTA). The h-ghrelin is represented in the figure as a black amino acid sequence, and red-letter substitution is that of the rat. Acyl ghrelin is proposed to initiate neurocircuits that promote feeding behavior in the ARC and VTA. Within the ARC, ghrelin stimulates neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons by binding to GHSR on their surface. Upon activation, these neurons produce and release γ-aminobutyric acid which inhibits anorectic proopiomelanocortin (POMC) neurons, decreasing the release of the anorectic peptide α-melanocyte-stimulating hormone (α-MSH). This efficiently reduces the amount of α-MSH capable of binding to satiety promoting melanocortin 4 receptors (MC4Rs). Simultaneously, activated NPY/AGRP neurons increase their production and secretion of orexigenic peptides NPY and AGRP. NPY binds to neuropeptide Y receptor type 1 (Y1R), and AGRP antagonizes the binding of α-MSH at MC4Rs. These two effects, the reduction in anorectic and enhancement of orexigenic peptides, work to reduce the activity of second-order anorexigenic neurons in the paraventricular nucleus (PVN) to promote homeostatic feeding behavior [66]. Similarly, ghrelin also stimulates VTA DA neurons, increasing the frequency and probability of the DA release from their projections in the nucleus accumbens (NAcc), prefrontal cortex (PFC), hippocampus, and amygdala to encourage mesolimbic reward feeding [66].

Figure 6

Brain pathways mediating ghrelin's effects on food motivation. The main pathway involved in food motivation is the midbrain DA projection from the VTA to the NAcc. Ghrelin appears to activate this pathway directly at the level of the VTA, which in turn gives a potential mechanism for ghrelin to promote food intake even when homeostatic hypothalamic centers such as the ARC or lateral hypothalamic area (LHA) indicate a state of satiety. Ghrelin also affects food motivation indirectly by activating an afferent pathway. At the level of the VTA, opioid signaling (but not NPY signaling) is required for ghrelin's effects on food motivation.

Figure 7

Representation of assumed mechanistic pathways involving ghrelin and its respective receptors in hippocampal cells. The intracellular pathways leading to functional outcomes related to memory modulation are shown in red. HIP: hippocampus; MMP: matrix metalloproteinase; LTP: long-term potentiation; ERK: extracellular signal-regulated kinase; CREB: cAMP response element-binding protein; NOS: nitric oxide synthase; PI3K/Akt: phosphatidylinositol 3-kinase and protein kinase B [70].

Figure 8

The CNS ghrelin modulates hypothalamic fatty acid metabolism by activating sirtuin 1 (SIRT1) and AMPK, which in turn stimulates transcription factors essential for NPY/AgRP, which finally affects food intake. The hypothetical molecular step which has not been described is indicated by the red arrow. The question mark indicates a black box in the molecular events triggered after the activation of the GHSR1 and before sirtuin 1. UCP2: uncoupling protein 2; pCREB: phosphorylated cAMP response element-binding protein; FOXO1: forkhead box O1; NPY: neuropeptide Y; AgRP: agouti-related peptide [161].

Figure 9

CNS ghrelin increases adiposity by favoring peripheral lipid deposition. Ghrelin binds to its receptor and hypothalamic neuropeptides (NPY/AgRP vs. POMC), and thereby melanocortin receptors are likely involved in the lipogenic action of ghrelin. Red arrows indicate the hypothetical molecular steps which have not been described for the lipogenic action of ghrelin. POMC: proopiomelanocortin; SCD1: stearoyl-CoA desaturase-1 [161].

Figure 10

Biological impact and therapeutic use of ghrelin on immune cells and in various inflammatory disease states [216]. VCAM: vascular cell adhesion molecule; HMGB: high mobility group protein 1; MCP1: monocyte chemoattractant protein 1; CLP: common lymphoid progenitors; DC: dendritic cell; Mφ: macrophage; LSK: Lin⁻Sca-1⁺c-Kit⁺; ETP: early thymocyte progenitors; TREC⁺-: T-cell receptor excision circle.