# Metabolomics/Hormones/Ghrelin

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## Introduction

Ghrelin was recently discovered in 1999 by Masayasu Kojima and his colleagues as a hormone that stimulates appetite. It is known as the counterpart of the hormone leptin, which is made in fat tissue.$^2$ Both these hormones, when at low levels, provide the sensation of being full, scientifically known as satiation. Conversely, when these hormones are at high levels, hunger ensues. Therefore, ghrelin production is increased before a meal and then slowed afterwards.
Due to the effects of ghrelin on metabolism and hunger, it is a prominent target for development of anti-obesity treatments. It has been reported that immunization of rats against ghrelin resulted in decreased weight gain and adiposity relative to control rats; even though both groups consumed an equivalent amount of food. This and other experiments could someday lead to the possibility of a vaccine against obesity.$^1$
* The link to the right shows a graph of ghrelin levels in the blood before and after a meal. The graph is based on assays of plasma ghrelin in 10 humans during the course of one day.$^1$
Ghrelin is primarily produced by PD/1 cells in the fundus of the stomach and epsilon cells of the pancreas.$^2$ Smaller amounts are also produced in the kidney, placenta, hypothalamus and the pituitary gland. This hormone exists in two forms; an endocrinological inactive (pure peptide) form, as well as an active (octanoylated) form. Without proper control of ghrelin production, disease states such as anorexia nervosa and Prader-Willi syndrome result. To prevent these disease states, regulatory mechanisms are required to maintain equilibrium. These mechanisms control ghrelin production and use the hormone for a number of vital needs.
The main function of ghrelin is to let the brain know the current energy-state of the body. In doing this, ghrelin helps balance the energy in our system. It is able to do this by promoting the secretion of growth hormone by activation of the growth hormone secretagoue receptor, and antonymously suppressing fat utilization in adipose tissue. Ghrelin is also known to stimulate gastric emptying. The hormone furthermore contributes to neurotrophy, particularly in the hippocampus; and it is essential for cognitive adaptation to changing environments and the process of learning. Most recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.$^2$ Ghrelin can also have positive effects on the cardiovascular system, although scientists are not sure if, for example, cardiac output is increased due to ghrelin or the indirect effect of its stimulation of growth hormone secretion.$^1$

# Discovery

Ghrelin was recently discovered in 1999 by Masayasu Kojima and his colleagues as a hormone that stimulates appetite.
More recently, Scripps research scientists developed an anti-obesity vaccine. The vaccine uses the immune system's antibodies to bind to selected targets, directing the body's own immune response against them. This method prevents ghrelin from reaching the central nervous system, thus resulting in reduction of weight gain.$^2$

# Physiology

Ghrelin is primarily produced by PD/1 cells as a preprohormone, then proteolytically processed to yield a 28-amino acid peptide in the fundus of the stomach and epsilon cells of the pancreas.$^2$ Smaller amounts are also produced in the kidney, placenta, hypothalamus and the pituitary gland. Ghrelin is also produced by a small number of neurons in the arcuate nucleus.
Receptors for ghrelin were discovered before the actual hormone. They are found on neurons in the arcuate nucleus and the ventromedial hypothalamus as well as the pituitary gland, heart and adipose tissue. These receptors are G protein-coupled receptors, also known as GHS receptors (growth hormone secretagogue receptors); and when activated by ghrelin, secrete growth hormone and have also been found to suppress fat utilization in adipose tissue.
This hormone increases food intake and fat mass by action in the hypothalamus. Here in the hypothalmus, ghrelin activates the arcuate nucleus cells. The ghrelin-response of these cells is affected by both leptin and insulin (other hormones related to metabolism).$^2$
Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the pleasurable and reinforcing aspects of natural rewards; for example, food, as well as addictive drugs, such as ethanol.$^2$

## Function/Purpose

The main function of ghrelin is to let the brain know the current energy-state of the body. In doing this, ghrelin helps balance the energy in our system.
It does this in a number of ways:
* Promotion of secretion of growth hormone by activation of the growth hormone secretagoue receptor.
* Suppression of fat utilization in adipose tissue.
* Stimulation of gastric emptying.
* Contribution to neurotrophy (within hippocampus)
* Essential for cognitive adaptation to changing environments.
* Essential to the process of learning.
* Activation of the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.$^2$
* Ghrelin may also have positive effects on the cardiovascular system, although scientists are not positive this is directly related to ghrelin.

### Energy Homeostasis

Afferent signals that arise from peripheral tissues are known to play a significant role in the CNS/periphery interactions that are involved in energy homeostasis regulation. Ghrelin is among the list of exemplifiers for this signaling and regulation. Ghrelin has been discovered to be primarily synthesized in the stomach and has become a focus of obesity research. This is because it is the only known systemic signal that specifically promotes food intake, positive energy balance, and the facilitation of adiposity development via attenuation of fatty oxidation. Researchers have proven that the action of ghrelin increases food intake, and independently regulates adipocyte metabolism. Ghrelin channels nutrient partitioning toward fat storage via favoring the uptake of glucose and triglycerides. This is made possible by increasing lipogenesis via lipid oxidation inhibition within white adipocytes. Central ghrelin administration also results in lower body core temperatures.
It has been determined that maximum ghrelin potency as a fat storage-promoting factor requires that it affects nutrient intake and metabolic nutrient partitioning. This is because the most significant ghrelin-induced body fat gain occurs with ample substrate availability, strong orexigenic drive and high efficiency lipid storage.
Ghrelin action elicits within the brain, which suggests that stomach-derived ghrelin may act at the level of brain structures to affect peripheral adipocytes metabolism, if secreted in substantial amounts. As a result, researchers have suggested that ghrelin may “prime” adipose tissue to store energy as fat after altering the expression of adipocyte enzymes.
Ghrelin gene deficiency has, in the past, been proven to decrease the respiratory quotient (RQ), which results in decreased fat deposition. A possible explanation for this may be decreased expression of lipogenic enzymes in white adipose tissue (WAT). Researchers propose that during a normal diet, limited lipogenic pathway activity of ghrelin knockout (KO) mice is sufficient for physiological phenotype maintenance. By contrast, it is also proposed that conditions of abundant dietary fat result in impaired adipocyte metabolism, which decreases the susceptibility for diet-induced obesity.
It is presumed that ghrelin may inhibit a food-induced insulin response, since ghrelin has an inhibitory effect on insulin secretion.
Researchers have concluded that a neuroendocrine network in the CNS that involves ghrelin, its hypothalamic target neurons, and the sympathetic nervous system are direct regulators of adipocyte energy metabolism. Researchers have hypothesized that the enzymatic deficiency of ghrelin deficient mice provides enough lipid storage capacity to manage low amounts of nutritional lipids that have been ingested while on a normal diet. It is determined that ghrelin-deficiency exhibits defective regulation of lipid-metabolizing enzymes, which impairs nutrient partitioning and efficient lipid deposition. However, it is assumed that protection against diet-induced obesity may partly result from the enzymatic capacity of ghrelin acting as a limiting factor for fat storage from circulating lipids.
Link to article:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16767221

## Mechanisms

Ghrelin is a peptide that promotes appetite by affecting the hypothalamic arcuate and paraventricular (PVN) nuclei which work in regulating the appetite.$^4$ The orexigenic neuropeptide Y/agouti-related protein neurons are stimulated while the anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript neurons are inhibited by ghrelin.$^4$
Inhibited by leptin and α-melanocyte stimulating hormone and activated by ghrelin and cannabinoids, hypothalamic AMPK mediates many appetite-regulating hormones.$^4$ The CB1 receptor in the hypothalamus is a route found to increase food intake when accessed by cannabinoids.$^4$
A signaling cascade has been suggested such that ghrelin→endocannabinoid→CB1→AMPK→appetite.$^4$
An increased release of endocannabinoids, acting through CB1, is needed for ghrelin to stimulate AMPK and appetite.$^4$ The presence of CB1 is also needed for the hypothalamic neurophysiological effects of ghrelin.$^4$ The orexigenic and central AMPK-stimulatory effects of ghrelin are mediated through the necessary endogenous cannabinoid system.$^4$

## Disorders Related to Ghrelin

Levels of circulating ghrelin are inversely correlated with positive energy balance, body mass index, body fat mass, adipocyte size, and leptin levels.$^3$
Anorexia nervosa patients exhibit high levels of ghrelin opposed to obese patients who have low levels of plasma ghrelin.$^3$ It is thought that the fluctuations of circulating ghrelin levels may mirror physiological adaptation to changes in energy balance. Treating obesity with a ghrelin antagonist seems like the right move because of the orexigenic and adipogenic attributes of ghrelin. Even though this seems logical it is not clear whether quenching ghrelin would have any positive effect on the already depressed ghrelin levels in obese patients. Also, like in many body systems there would be counter mechanisms that would be activated in order to satisfy nutritional needs. Ghrelin also has a strong stimulatory effect on Growth Horomone (GH) secretion and an antagonist could drop off GH levels below functioning levels.$^3$
Obesity has been linked to the ghrelin gene having genetic variations.$^3$ Baseline levels of ghrelin were more alike in pairs of monozygotic twins than in heterozygous pairs. Also, the decrease in ghrelin concentration after periods of overfeeding showed the same trend.$^3$ Clinical uses for ghrelin can be fabricated once a better understanding of its stimuli and regulatory pathways for synthesis and release are known.$^3$

# Resources:

WEB:
=1.= http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/gi/ghrelin.html
Ghrelin Overview
== This page covers the structure of ghrelin and its receptors, the control and physiological effects of ghrelin, and disease states that are a result of high or low levels of ghrelin. It is a page made at Colorado State University that delves into information regarding growth hormone secretagogue receptor (GHS-R), Prader-Willi syndrome, anorexia nervosa, as well as many functions of the hormone. The production of an anti-obesity vaccine is also discussed. The page contains a good graph to show how ghrelin concentrations change throughout the day. Although the page is short, it contains a generous amount of good information regarding ghrelin and its properties. ==
New words encountered are: (all definitions from dictionary.com)
preprohormone - A preprohormone is the precursor protein to one or more prohormones, which are in turn precursors to peptide hormones. The protein generally consists of the amino acid chain that is created by the hormone secreting cell, before any changes have been made to it.
proteolysis - Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion.
n-octanoic acid - also known as caprylic acid, CH3 (CH2)6 COOH
fundus - Latin for "bottom", fundus is a generic anatomical term referring to the portion of an organ opposite from its opening.
secretagogue - A secretagogue is a substance which causes another substance to be secreted.
somatostatin - Somatostatin (also known as growth hormone inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.
adiposity - Excessive accumulation of lipids in a site or organ. (Obesity)
anorexia nervosa - an eating disorder characterized by an extreme reduction in food intake leading to potentially life-threatening weight loss. This syndrome is marked by an intense, irrational fear of weight gain or excess body fat, accompanied by a distorted perception of body weight and shape.
Prader-Willi syndrome - Prader-Willi syndrome (PWS) is a genetic condition caused by the absence of chromosomal material from chromosome 15. Characteristics of the syndrome include developmental delays, poor muscle tone, short stature, small hands and feet, incomplete sexual development, and unique facial features. Insatiable appetite is a classic feature of PWS. This uncontrollable appetite can lead to morbid obesity and behavior disturbances.
Voracious - exceedingly eager or avid
== This website relates to our class by covering topics such as hormones, hormone receptors, the control and regulation of hormones, as well as the effects of uncontrolled regulation. ==
=2.= http://en.wikipedia.org/wiki/Ghrelin
Ghrelin Overview
-- This page contains a general overview of ghrelin, the history of ghrelin, its mechanism of action and role in disease, the different forms of ghrelin, its relation to obestatin (similar hormone), and information regarding an anti-obesity vaccine. It is a wikipedia page, so the information comes from a number of sources. Ghrelin's actions in the arcuate nucleus and the ventromedial hypothalamus are discussed, as well as its role in the hippocampus. This page also covers ghrelin related diseases such as anorexia nervosa, obesity, and Prader-Willi syndrome. The page also discusses a recently produced vaccine for obesity. This page contains a lot of good information on ghrelin. Since it is a wikipedia page there is information compiled from a number of resources. --
New words encountered are: (all definitions from dictionary.com)
leptin - a hormone that is thought to suppress appetite and speed up metabolism.
bariatric - a branch of medicine that deals with the control and treatment of obesity and allied diseases.
neurotrophy - the influence of the nerves on the nutrition and maintenance of body tissue.
octanoylated - the active form of ghrelin.
mimetics - characterized by, exhibiting, or of the nature of imitation or mimicry. (mimic or make-believe.)
hedonic - of, characterizing, or pertaining to pleasure.
cachexia - general ill health with emaciation, usually occurring in association with cancer or a chronic infectious disease.
arcuate nucleus - Any of various specialized groups of nerve cells in the medulla oblongata, thalamus, or hypothalamus of the brain.
kinases - Any of various enzymes that catalyze the transfer of a phosphate group from a donor, such as ADP or ATP, to an acceptor.
endothelial - The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall.
== This website relates to our class by covering topics such as hormones, hormone receptors, active and inactive complexes, mechanisms of the control and regulation of hormones, and the effects of uncontrolled regulation (diseases). ==
Journal Articles:
=3.=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1356251
Ghrelin Overview
==This article discusses the activation of ghrelin via the vagus nerve. Its effects are seen in obesity, eating disorders, neoplasia, and cachexia. Ghrelin acts as a ligand for the growth hormone secretagogue receptor (GHSR) and has also been seen as an independent pathway in regulating GH release. Physiologic homeostasis is maintained through ghrelin's brain-gut peptide role which emphasizes the afferent vagal fibers being the major brain pathway. The article also suggests the importance of ghrelin's role in enhancing immune responses and down-regulating anti-inflammatory molecules. Ghrelin's functions must be pinpointed in order to use ghrelin in diagnosis and treatment of different diseases related to over-nutrition and catabolism as a result of surgical trauma.
New words encountered are: (all definitions from dictionary.com)
oxyntic - Forming or secreting acid, as the parietal cells of gastric glands.
somatotroph - A cell of the anterior lobe of the pituitary gland that produces somatotropin.
gonadotrophin - A substance formed in the anterior pituitary gland that affect the activity of the ovary or testis.
anxiogenic - Causing anxiety.
orexigenic - Having a stimulating effect on the appetite.
hyperleptinemia -Increased serum leptin level.
etiology - The cause or origin of a disease.
apoptosis -Disintegration of cells into membrane-bound particles that are then eliminated by phagocytosis or by shedding.
adenoma - A benign tumor originating in a secretory gland.
isoform - Any of two or more functionally similar proteins that have a similar but not identical amino acid sequence and are either encoded by different genes or by RNA transcripts from the same gene which have had different exons removed.
==This article relates to class because of its examples of regulation. Although ghrelin's regulation is still highly unknown, ghrelin has large regulatory effects.
=4.=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2258435
Ghrelin Overview
This article discusses the mechanism of the ghrelin-cannabinoid interaction. Both ghrelin and cannabinoids enhance the appetite by activating the hypothalamic AMP-activated protein kinase. The study in this paper involved adult male WT mice and CB1-KO mice. The study showed that the CB1 receptor is needed for ghrelin's appetite stimulating response. The cannabinoid content of the hypothalamus is increased by gherelin and this effect also involves CB1. Input into the PVN is inhibited by ghrelin. Although, a CB1 antagonist as well as inhibiting cannabinoid synthesis can be used to prevent this effect. Ghrelin's appetite-inducing effects are dependent on the interactions between ghrelin and the cannabinoid systems.
New words encountered are: (all definitions from dictionary.com)
endogenous - Growing or developing from within; originating within.
cannabinoid - Any of various organic substances, such as THC, found in cannabis.
putative - Commonly regarded as such; reputed; supposed
electrophysiology - The branch of physiology dealing with the electric phenomena associated with the body and its functions.
retrograde signaling - A phenomenon in which a signal travels from a postsynaptic neuron to a presynaptic one.
parvocellular - Characterized by relatively small cell bodies.
glucocorticoid - Any of a group of steroid hormones, such as cortisone, that are produced by the adrenal cortex, are involved in carbohydrate, protein, and fat metabolism, and have anti-inflammatory properties.
melanocortin - A group of pituitary peptide hormones that include adrenocorticotropin (ACTH) and the alpha, beta and gamma melanocyte-stimulating hormones (MSH) that derive from the prohormone proopiomelanocortin.
intraperitoneal - Situated within or administered by entering the peritoneum.
stereotactic - Movement of an organism in response to contact with a solid.
==This article relates to class because it shows the effect and importance of signaling cascades where a product in one reaction is necessary for subsequent reactions.