Gut-brain signalling

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Introduction

Obesity is becoming a growing problem throughout the world and for this reason significant research has been undertaken to increase in the knowledge of the physiological and molecular mechanisms which effect and control body mass. In order to regulate these mechanisms complex interactions between different systems take place. This article addresses the interaction between the gastrointestinal tract and the brain and how secretion of varying hormones from different areas of the body causes appetite enhancing and satiety signals to be sent to the brain. The main hormones which have been most intensely examined are: Ghrelin, obestatin, CCK, GLP-1, PYY and insulin which all play a major role in appetite regulation. The vagus nerve is also a key mediator of regulation and is highly involved signalling, and all of these inputs are processed by areas in the brain such as the hypothalamus and the nucleus tractus solitarius (NTS).

Title of Subpart 1

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'''Cholecystokinin'''

Cholecystokinin (CCK) is a peptide hormone synthesised and secreted by L-cells in the mucosal epithelium of the duodenum, it is released in response to the presence of partially digested lipids and proteins. It inhibits gastric emptying and stimulates the release of digestive enzymes from the pancreas and bile from the gall bladder by acting at the CCKA receptor (mainly found in the periphery but also found in some areas of the CNS). Because gastric emptying is inhibited, the partially digested lipids and proteins are exposed to the digestive enzymes and bile so are further broken down. As the lipids and proteins are broken down, CCK secretion is reduced as there is no longer a stimulus.

CCK is one of the most abundant neuropeptides in the CNS. It acts as a hunger suppressant by activating CCKB receptors found throughout the brain. It mediates satiety and can cause anxiety and nausea.

CCK acts as a ‘gatekeeper’ for the response of other gut-brain signalling hormones on the afferent vagal neurons. At low levels (after fasting) CCK stimulates the expression of certain receptors associated with the stimulation of food intake (melanin concentrating hormone (MCH)-1 and cannabinoid CB1 receptors). At high levels (after food consumption) the MCH-1 and CB1 receptors are down regulated. Therefore CCK present at a high or low concentration can effect how the afferent vagal neurons respond to other neuro-hormones.

In rats it has been found that CCK inhibits food intake in younger individuals more effectively than in older individuals. It also has a greater effect in males than in females.

'''Glucagon-like peptide-1'''

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted from L-cells in the mucosal epithelium of the duodenum and small intestine. It is derived from the pro-glucagon gene product and is released into the circulation in response to the presence of nutrients. It acts at the pancreas where it stimulates insulin release and suppresses glucagon release (because of these actions it is under investigation as a potential treatment for diabetes). It also increases insulin sensitivity.

GLP-1 also acts on an inhibitory subset of neurons in the arcuate nucleus (part of the hypothalamus) via the brain stem (this eliminates the blood-brain barrier). Activation of these inhibitory neurons induces satiety and decreases food intake/hunger. It also decreases gastric emptying so adds to the feeling of being ‘full’. At higher concentrations GLP-1 causes nausea, and can induce Conditioned Taste Aversion (CTA) where the brain associates the taste of a certain food with being toxic (usually occurs when an individual consumes a food that had made them sick).

In obese individuals, GLP-1 secretion is decreased. When weight is lost in obese individuals GLP-1 secretion returns to normal (so GLP-1 could contribute to the pathogenesis of obesity). GLP-1 receptor agonists have been targeted as a potential therapy for obesity. GLP-1 itself is not suitable as a clinical treatment for obesity as it has a very short half life (approximately 2 minutes) making storage impossible.

'''Obestatin'''

Obestatin is a sibling of ghrelin from preproghrelin identified in 2005. Obestatin is found in the stomach with the majority of obestatin producing cells found in the basal part of the mucosa. Unlike ghrelin, obestatin works by inhibiting food intake and therefore opposes the effects of ghrelin. Obestatin reduces body weight gain, gastric empting, and also suppresses intestinal motility. Furthermore studies have produced evidence that obestatin also has further physiological functions including regulation of energy homeostasis, cell proliferation, hormone secretion and inhibition of thirst. It is still unclear obestatin’s role in gut-brain signalling and the mechanisms that result in its inhibition of appetite.

Orexigenic Signals

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Ghrelin

Ghrelin is a 28-amino acid brain-gut peptide -cleaved from preproghrelin. It is synthesised and secreted primarily by endocrine cells in the stomach, with appetite inducing activities. Initially Ghrelin was identified as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Endogenous levels of ghrelin change according to nutritional status; with levels increasing during fasting and immediately decreasing after food intake, providing evidence that it may be involved in food initiation. Administration of Ghrelin (centrally and peripherally) results in appetite stimulation and increased food intake. Circulating levels of ghrelin are found to be lower in obese people and is therefore negatively correlated with BMI.

Ghrelin is able to cross the blood-brain barrier with its effect on eating behaviour being mediated via the arcuate nucleus and solitary tract nucleus to merge in the hypothalamus, suggesting the molecule may have central endocrine actions. It opposes the actions of leptin through the disinhibition of appetite stimulating neuropeptide Y (NPY) and agouti gene-related peptide (AgRP)

Ghrelin also influences many other biological actions including effects such as gastrointestinal (GI) motility-stimulating gastric emptying, cardiovascular function, immunity, inflammation, pancreatic function, hormone secretion and memory amoung others. This is due to the GHS-R being expressed widely throughout the brain and peripheral tissues. It is still thought to be unclear by what mechanism and to what extent ghrelin plays a role in food initiation; however it is suggested ghrelins orexigenic activities may depend upon the gastric afferent vagal nerve.

Title of Part 2

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Title of Part 3

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