Question

To maintain a stable weight, there must be energy balance. Energy intake is equal to energy expenditure. However, when this energy balance is disrupted it can lead to individuals who are underweight or overweight. Maintaining proper energy balance involves complex interactions among several organ systems in the body. In the hypothalamus there is a satiety center and a hunger center. Leptin is an anorexigenic (i.e., satiety) signal, whereas ghrelin is an orexigenic signal (i.e., promotes appetite). Leptin is a peptide hormone produced by adipocytes. Ghrelin is a peptide hormone produced by gastric cells in the stomach. There are leptin receptors and ghrelin receptors in the hypothalamus.

Question: From its point of origin, trace how a molecule of ghrelin will move through the circulatory system (including through the heart) and ultimately bind to a receptor in the hypothalamus (nervous tissue).

Answer 1

Ghrelin is an orexigenic peptide predominantly secreted from the stomach and stimulates appetite and growth hormone (GH) release. Studies have provided evidence that ghrelin exercises a wide range of functions, including regulation of food intake and energy metabolism, modulation of cardiovascular function, stimulation of osteoblast proliferation and bone formation and stimulation of neurogenesis and myogenesis. In the gastrointestinal system, ghrelin affects multiple functions, including secretion of gastric acid, gastric motility and pancreatic protein output. Most of these functions have been attributed to the actions of acylated ghrelin. The balance among its secretion rate, degradation rate and clearance rate determines the circulating level of ghrelin. This review explains what ghrelin is, its physiological functions and the factors that influence its level.

Movement of molecules in circulation & Receptors:

GHS-R1b mRNA is as widely expressed as ghrelin, whereas GHS-R1a gene expression is concentrated in the hypothalamus–pituitary unit, although it is also distributed in other central and peripheral tissues. Centrally, in areas of the central nervous system (CNS) that affect biological rhythms, mood, cognition, memory and learning, such as the hippocampus, pars compacta of the substantia nigra, ventral tegmental area (VTA), dorsal and medial raphe nuclei, Edinger–Westphal nucleus and pyriform cortex.However, published descriptions of the distributions of ghrelin-like immunoreactivity in the CNS are inconsistent.

Peripherally, the GHS-R1a gene is expressed in the stomach, intestine, pancreas, thyroid, gonads, adrenal, kidney, heart and vasculature, as well as several endocrine tumours and cell lines, and have been found to express GHS-R1a with negligible binding found in the parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon and spleen. This wide distribution of GHS-R1a indicates that the ghrelin and synthetic GHS possess broader functions beyond the control of GH release and food intake.

Growth Hormone-releasing Effect

The GH-releasing effect of the ghrelin occurs through direct effect of ghrelin on pituitary somatotroph cells, synergistic effect with GHRH and through stimulation of vagal afferents. In high doses, ghrelin may also stimulate prolactin, corticotropin and cortisol secretion in humans.

Orexigenic Effect (Appetite-stimulating Effect)

Ghrelin is the only known orexigenic gut peptide. The pre-prandial elevation of ghrelin levels and its fall after meals led to the notion that ghrelin was a ‘hunger’ hormone responsible for meal initiation. Ghrelin is involved in short-term regulation of food intake and long-term regulation of bodyweight through decreasing fat utilisation.The effect of ghrelin on feeding is mediated through the GHS-R1a, as indicated by the lack of its orexigenic effect in GHS-R knocked out mice.GHS-R1a is highly expressed in hypothalamic cell populations that regulate feeding and bodyweight homeostasis.

In the arcuate nucleus (ARC), the ghrelin-containing neurons send efferent fibres onto neuropeptide Y(NPY) and agouti related peptide (AgRP)-expressing neurons to stimulate the release of these orexigenic peptides. Ghrelin has also been reported to inhibit the firing of proopiomelanocortin (POMC) neurons by increasing the frequency of spontaneous synaptic γ-aminobutyric acid (GABA) release onto them in a pattern representing a functional antagonism to leptin, without affecting POMC mRNA expression. Confirming that ghrelin’s orexigenic effect is mediated by specific modulation of AgRP/NPY neurons in the ARC, no change was demonstrated in the mRNA levels of the other feeding– promoting neuropeptides such as melanocyte stimulating hormone (MCH) and prepro-orexin (OX). Recent data indicate that the orexigenic effect of ghrelin is mediated by its modulation of hypothalamic adenosine monophosphate (AMP)-activated protein kinase (AMPK) enzyme activity.

The detection of ghrelin receptors on vagal afferent neurons in the rat suggests that ghrelin signals from the stomach are transmitted to the brain via the vagus nerve.However, whether integrity of the vagus nerve is crucial for effects of ghrelin and whether vagotomy prevents its orexigenic effect in animal models and humans is not universally accepted, as cutting vagal afferents were not necessary for the orixigenic effect of the peripherally injected ghrelin in rats, and gastrectomy in humans accompanied by vagatomy did not prevent the orexigenic effects of ghrelin treatment, indicating an intact vagus is not required for its orexigenic effects.