Gut-brain signalling

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).

Anorexic Signals
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 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.

Peptide YY (PYY)

PYY is a 36- amino acid peptide that is secreted from endocrine cells (L-cells) in the ileum and colon. gaining it name from the amino acid tyrosine residues (“Y”) being found at the ends of its structures. PYY3-36 is dominant in the two endogenous forms in circulation with both affecting different Y-receptors found through out the central nervous system, including the vagal nerve and within different brain regions, particularly the brain stem and hypothalamus.

PYY has low circulation levels in a fasting state, but upon food intake, particularly high preotein meals, rapidly increases (within 15 min) until a peak at 1-2 hours after the meal. It acts as an "ileal brake" to delay gastric emptying. (5*)

PYY has is mostly associated with satiety regulation where high levels correlate with high satiety It has been shown to reduce feeding in rodents and humans, a correlation has been proven between high levels of PYY and low markers of adiposity (1)and Obese mice have been found to have low PYY circulation levels It is thought to be a factor involved in food intake reduction after bariatric surgery. Guo et al (2006) also found a negative correlation between PYY circulation levels and waist circumference, suggesting it as a contributing factor to energy expenditure and lipid metabolism. PYY3-36 expression has also been shown to be affected by other areas of the brain, namely those connected with reward and pleasure - PYY may be the ‘switch’ between homeostatic and pleasure controlled eating.

Insulin

Insulin is a hormone secreted into the blood by the pancreatic β-cells in response to glucose intake. Increased glucose causes secretion of other gut hormones, Glucose-Dependent Insulinotrophic Peptide (GIP) and Glucagon-Like Peptide-1, which directly cause the secretion of Insulin from the Pancreas. With receptors in the hypothalamus, including the Arcuate Nucleus (ARC), cerebellum, cortex and hippocampus, Insulin signalling in the brain causes a reduction in food intake and body weight In the ARC, it causes increased synthesis of POMC and inhibits NPY plus AgRP production, therefore increasing appetite inhibition. Insulin also enhances the efficacy of systemic CCK in the brain to reduce overall food intake. Reduced levels in insulin results in increased eating and weight gain.

Insulin plays an important long-term role in energy homeostasis and metabolism control. Its secretion levels also correlate to the degree of adiposity within the subject ; therefore acting as a continuous message to the brain concerning the amount of fat within the body and contributes to the overall long term regulation of bodily energy homeostasis. Insulin signalling in the ARC directly affects the liver via the vagus nerve, inhibiting endogenous glucose production and facilitating glucose uptake by the muscles, liver and other tissues. It also promotes fat storage as triglycerides and prevents fat breakdown thus inhibiting fat oxidation and further promoting glucose uptake in cells.

(1) Broberger, C. (2005) Brain regulation of food intake and appetite: molecules and networks. Journal of Internal Medicine 258: 301-327 (2)Woods, S.C., Benoit, S.C and Clegg, D. J (2006) The Brain-Gut-Islet Connection Diabetes 55: 114-121 (3)THESIS? Heijboer, Annemieke Corine (2006) Insulin sensitivity: modulation by the gut-brain axis. Department Endocrinology, Faculty of Medecine, Leiden University Medical Center, Leidn University. (4)Woods, S.C et al (1996) The evaluation of Insulin as a Metabolic Signal Influencing Behaviour via the Brain Neuroscience and Biobehavioural Reviews 20:139-144 (5) Badman, M.K. and Flier J. S (2005) The Gut and Energy Balance: Visceral Allies in the Obesity Wars Science 307: 1909-1914 (6) Wook, Kim and Egan, J.M. ( 2008) The role of incretins in Glucose and Hemeostasis and Diabetes Treatment Pharmacology review 60:470-512 (7) Boon, N.A. et al (2006) Davidson’s Principles and Practice of Medicine Elsevier Limited, Edinburgh

Orexigenic Signals
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.

Role of the Vagus Nerve
Signalling from the gut can be both neural and hormonal. The role of vagal afferent neurones, which are found throughout the gastrointestinal system, is a key area of research to understand eating behaviours and tackle the obesity epidemic. Neural communication from the gut begins with the stomach; where afferent fibres are widely distributed to detect distension and stretch of the stomach walls. The hormones released by the stomach and intestines have been shown to mediate appetite and satiety signals in the brain by travelling via the circulation or receptor activation on vagal afferent neurons. There have been many identified receptors present on the afferent neurons which can allow for this (Dockray,2009). These receptors include the CCK1 receptor for cholecystokinin, the PYY receptor Y2 and GHS-1 which binds ghrelin. The review by Dockray discussed the finding of how the vagal afferent neurons alter the expression of receptors on the membrane in relation to CCK concentrations; results showed that administration of CCK to fasted rats increased the expression of the Y2 receptor. This property of CCK therefore allows it to sensitize the vagal afferent neurons to appetite signalling and satiety signalling.

Neuropeptide Y (NPY) and Agouti-Related Protein
Neuropeptide Y (NPY) and Agouti related protein (AgRP) are both stimulators of appetite, with NPY being the most powerful known to date (Naslund, 2007). These neuropeptides are located in the arcuate nucleus of the hypothalamus and also the NTS for NPY (Smith, 2008). AgRP is the endogenous inverse agonist of melanocortin receptors (Kas et al, 2005). One key mechanism by which NYP/AgRP expressing neurons increase appetite is by antagonising α-MSH by binding to its receptor MC4R (Luquet et al, 2005), as α-MSH is the most potent appetite inhibitor to be found. An interesting study by Luquet et al showed that using the human diphtheria toxin receptor to only be expressed on AgRP locus in mice, injection of diphtheria toxin will abolish that gene, resulting in the loss of AgRP and NYP as they are co-localised in the same neurons. When done in neonates it was found that they were able to compensate for the loss and when adults they had normal body weight and appetite. However when this was performed on adult mice they lost all appetite stimulation, showing that the system is highly complex and can perform without these neuropeptides. This brief summary of NPY and AgRP only describes the simple mechanisms of how they act and of their function. They have been linked to many other roles as well as appetite stimulation including regulation of stress responses due to their interaction with the PVN. Their full range of mechanisms of action has to be understood in much greater detail for them to be a target for obesity treatment and appetite control.