The Genetics Involved In Obesity Biology Essay

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Obesity is an extremely prevalent condition that is putting an increasing strain on global health resources. In 1995 it was estimated that the number of obese adults worldwide was 200 million and this number had grown by the year 2000 with a rise of a further 100 million [i] . In 2008 in the United Kingdom it was reckoned that 61.4% of adults were either overweight or obese with 24.5% of these having a BMI of over 30 [ii] . Thought previously as a problem of just high-income countries, obesity is now regarded as a condition that affects countries of all economic statuses [iii] . It is a significant risk factor for various chronic conditions including diabetes, cardiovascular disease and cancers [iv] , costing the NHS £4.2billion directly which is estimated to double if nothing is to change by the year 2050 2(DH:OBGI).

The cause of obesity appears simple; a positive imbalance of energy intake to energy expenditure. It is a chronic condition that progresses through an unhealthy diet and the patient's choice of a poor lifestyle [v] . The causes of these however depend upon environmental and genetic influences as well as drugs and disease.

In terms of genetics, humans have evolved under conditions where periods of food scarcity were common and to obtain food took significant effort and exercise. The capability to store energy in adipose tissues was incredibly advantageous in these times. [vi] However in recent years, especially in more developed countries, food has become more plentiful, much easier to acquire and has a greatly increased fat content. This has led to cause the energy balance to tip unfavourably in many individuals who would have been relatively well genetically adapted thousands of years ago but are now regarded as unhealthy and at higher risk of early mortality. Genes that predispose an individual to a higher risk of obesity include those that regulate the fat stores themselves and those which stimulate feeding behaviour. One of these latter genes codes for the Neuropeptide Y (NPY) receptors of which research has been undertaken into their potential as anti-obesity drug targets.

It is clear that obesity is an exponential problem and that measures need to be taken to try and reduce the impact that it is having upon the population. Recommended management of overweight/obese patients always begins with changes in their diet and lifestyle. This involves switching to a sustainable, healthy regime that suits the patient. Losing this weight however is extremely difficult for some patients due to their genetic makeup and/or physical barriers such as income, disability or self-esteem [vii] . For these patients anti-obesity agents could potentially be very beneficial and prevent the need for invasive surgical procedures. There are a few drugs currently available to combat obesity; however they tend to come with side effects. The NPY receptors offer a novel target for treatment and it is this group of receptors that are discussed in this text.

2. Importance of Leptin

Studies have been carried out on mice to investigate the genetics of obesity. Transgenic ob/ob and db/db mice have shown the importance of the satiety hormone leptin. Leptin is produced by adipocytes and acts upon the central nervous system (CNS) in relation to the long-term stores of body fat. A significant area of leptin action regarding energy homeostasis is in the arcuate nucleus (ARC) in the hypothalamus where a large number of leptin receptors are expressed [viii] . Here it modulates the activities of different neurons including NPY, agouti-related peptide (AgRP), proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) neurons [ix] . Normally, if the long term stores are adequate then there is a

Figure 1: Role of arcuate nucleus neurons in adiposity signalling, activity of leptin/insulin-sensitive adiposity signalling pathways in hypothalamus under conditions of leptin/insulin deficiency.

M Schwartz et al: Central nervous system control of food intake (Nature, April 2000, vol 404:661-671)

greater presence of leptin leading to inhibition of NPY and activation of POMC neurons which in turn inhibits feeding and indirectly lowers body mass due to satiety [x] and vice versa for when the stores are low (fig. 1).

In the case of the ob/ob mouse, it has a spontaneous point mutation in the leptin gene which prevents production of the hormone so are therefore leptin deficient [xi] . Therefore there is no excitation of POMC neurone and no inhibition of NPY neurons which explains the symptoms that these mice exhibited. They became obese as well as having symptoms of high insulin in the blood, intolerance to glucose, hyperglycaemia and hyperphagia [xii] . As for the db/db mice, these had a point mutation in the gene for the leptin receptor (LEPR gene). This meant that they were LEPR deficient and thus showed similar symptoms including obesity due to the fact that leptin as unable to exert its effects in the ARC [xiii] .

However, leptin levels are often chronically high in patients with obesity which is associated with attenuated ability of the LEPRb to trigger the pathways needed for interaction with NPY/POMC neurons [xiv] . Therefore using leptin as an anti-obesity drug is not that effective due to this down-regulation of these receptors and leptin-resistance.

3. Current Anti-obesity agents

As mentioned earlier the management of obesity involves altering the patient's lifestyle, most importantly their diet and exercise levels. Only after these changes have shown no effect or there are significant comorbidities associated with the individual should other interventions, whether surgical or pharmacological, be considered. Often poor results from lifestyle changes are due to low compliance which is sometimes understandable considering what drastic alterations that some have to do to their lives.

From a pharmacological perspective there are two main classes of anti-obesity drugs. These are the anorexiants which target the CNS to suppress appetite and the periphery-acting lipase inhibitors which lessen the absorption of lipid into the gut [xv] . An example of an anorexiant is the drug sibutramine which is a joint noradrenaline/serotonin reuptake inhibitor which acts to produce satiety. Studies have shown [xvi] that it is effective at achieving weight loss and maintaining this. The side effects however are quite potent in that it can result in poorly controlled hypertension putting the patient at increased risk of stroke. This has led to the suspension of the market authorisation of sibutramine by the European Medicines Agency and thus is no longer prescribable in the United Kingdom [xvii] .

The only approved lipase inhibitor available for prescribing in the United Kingdom is Orlistat. By reducing fat absorption in the gut through inhibition of gastric and pancreatic lipase, orlistat works by preventing fat from entering the fat stores in the periphery. The loss of weight is often due to the patient taking actions to overcome the side effects of the drug [xviii] . The side effects include steatorrhoea, sudden need to defecate, diarrhoea, abdominal pain and flatulence [xix] . Therefore to try and minimise these patient's lower the fat content of the food that they take in and thus reducing their energy intake and losing weight. Problems may also occur with fat-soluble vitamin deficiencies so supplementation is often recommended. Orlistat is now available over the counter, however if no weight loss has occurred after 12 weeks patients are recommended to stop using it and treatment should last no longer than 6 months [xx] .

After having tried lifestyle changes and orlistat but no weight was lost then there are further options. Surgery appears to be a quick-fix strategy. However bariatric surgery carries considerable risks to the patient. It is also an expensive answer to obesity so more pharmacological agents are currently being researched and investigated for the wider use. However it remains as the only beneficial treatment option for individuals who are morbidly obese.

4. Neuropeptide Y and the Pancreatic Polypeptide Family

Figure 2

Alignment of human neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP). Amino acid identities between peptides are indicated by a *.

(MC Michel et al: XVI. International Union of Pharmacology Recommendations for the Nomenclature of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide Receptors (Pharmacological Reviews, March 1998, vol 50 #1:143-150)

NPY, peptide YY (PYY) and pancreatic polypeptide (PP) are all from the same family of polypeptide. They are all made up of 36 amino acids have similar sequences to each other [xxi] (fig. 2) allowing them all to have a tertiary structure called the "PP-fold" [xxii] . This adaptation allows them to bind with their receptors.

NPY is found in multiple locations in the CNS as well as in the peripheral nervous system, predominantly in sympathetic neurons (XXI Michel 1998). It therefore acts as an important neurotransmitter. In the CNS, NPY contributes to a diverse range of physiological roles including: control of learning and memory; emotional and sexual behaviour; hormone secretion and modulation of knowledge and recall [xxiii] . NPY in the hypothalamus, especially the ARC, has been found to participate in energy homeostasis.

Figure 3 - Proposed mechanisms of stress-induced exacerbation of abdominal DIO by activation of the adipose tissue NPY-NPY2R pathway.

From the following article: Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome Lydia E Kuo et al., Nature Medicine 13, 803 - 811 (2007) Published online: 1 July 2007 Corrected online: 24 July 2007doi:10.1038/nm1611

In the periphery, the sympathetic neurons have been shown to release NPY under the influence of stress. The NPY and NPY Y2 Receptor become upregulated due to positive feedback resulting in an increase in abdominal fat and the development of metabolic-like syndrome and stress-induced obesity [xxiv] (Fig. 3).

In the CNS, NPY expression is predominantly confined to the ARC and also the dorsomedial hypothalamus (DMH). It is in the ARC that leptin influences the role of NPY whereas in the DMH it appears to be leptin-independent and expression is mainly influenced by chronic food restriction instead. Centrally administered, NPY causes substantial increases in food intake and body weight and can eventually result in obesity. However under leptin presence NPY mRNA expression is reduced and during periods of fasting expression is increased, corresponding to lower levels of circulating leptin. NPY in the ARC can therefore be seen as a downstream mediator of leptin's actions [xxv] . The NPY-ergic neurons in the ARC then project to the paraventricular nucleus (PVN) and the lateral hypothalamus (LH) where energy homeostasis in terms of food intake is centred. Less is known about how the DMH exerts its similar effects using NPY, but it is now thought to be involved with exerciseXXVBSHENG2007.

Unlike NPY which is purely a neurotransmitter, PYY and PP are predominantly hormones. PYY is primarily produced in intestinal endocrine L-cells. Two forms exist: PYY1-36 and PYY3-36. The former acts upon Y1, Y2 and Y5 receptors whereas PYY3-36 acts largely on the Y2 receptor but also upon the Y1 and Y5 receptors with low affinity as a result of the removal of 2 amino acids. PYY3-36 is produced from PYY1-36 by the enzyme di-petidyl peptidase IV. The balance of these two forms varies in humans according to the feeding status. After eating, PYY3-36 takes the major form in the bloodstream and after fasting, PYY1-36 is more prominent [xxvi] . The size and fat content of the food eaten further influence the levels of PYY3-36 [xxvii] . Therefore one can deduce that PYY3-36 can be seen as an anorexigenic hormone and PYY1-36 as an orexigenic hormone. How it is synthesised or released in the gastrointestinal tract is largely still unknown. It was also shown in rats to decrease the amount of food being consumed, suggesting it has a role in the suppression of appetite [xxviii] . This is further backed up with evidence that PYY3-36 levels are increased in anorexia nervosa patients [xxix] compared to those with a normal weight or who are obese. Interestingly, unlike leptin, it has been shown that those who are obese do not develop a resistance to PYY3-36 [xxx] , suggesting a therapeutic role in comparison to administration of leptin which has been proven to be less effective.

Similar to leptin, PYY3-36 acts in the CNS through inhibition of the NPY neurones in the arcuate nucleus of the hypothalamus however it also inhibits the POMC neurones to a certain extent [xxxi] . Its inhibitory effects are brought about by hyperpolarisation of these neurones which in turn reduce the firing. It is therefore understood that PYY3-36 role as an anorexigenic agent is more influenced by the inhibition of NPY neurons, due to inhibition of POMC suggesting an orexigenic quality. This suggests that PYY3-36 may play a more important role in other areas of the brain than it does in the ARC. However the overall effect on the individual is that it appears to reduce feeding when administered. Like leptin is a signal to the CNS for the amount of fat deposition, PYY3-36 is a signal for the CNS about the state of the energy stores in the periphery.

Pancreatic polypeptide (PP) is a 36 amino acid peptide created by the F cells in the pancreatic islets. Its levels in the circulation are raised after a meal, with the highest concentration after 30mins. The concentrations are influenced by the number of calories that were in the meal. It secretions are promoted by the vagal stimulation but also by other stomach hormones, exercise and distension of the stomach. Somatostatin reduces the secretions of the F-cells. Physiologically it prevents the emptying of the stomach, inhibits gall bladder motility and reduces the secretions of the exocrine pancreatic cells. In the CNS, pancreatic polypeptide seems to exert its effects largely in the brainstem, although expression of its main receptors (predominantly the Y4 receptor, but also has affinity for Y1 and Y5) is also found in the hypothalamic arcuate and paraventricular nuclei [xxxii] . The overall effect of this is to reduce feeding in the individual. Its anorectic activities are thought to be largely mediated through the vagus nerve (X) [xxxiii] . PP and PYY are both hormones of the gut and appear to have both peripheral and central effects on energy homeostasis in humans. Figure 4 shows a table of gut hormones and their effects on body weight regulation including PP and PYY

Figure 4: Overview of gastrointestinal hormones known to affect food intake

MT Leary & RL Batterham: Gut hormones: Implications for the treatment of obesity (Pharmacology & Therapeutics, 2009, 124:44-56)

5. Y Receptors

There are a minimum of 5 receptors for NPY, these being the Y receptors (Y1, Y2, Y4, Y5 and Y6) [xxxiv] . They are classified as G-coupled receptors and therefore are excited by increase in the concentration of calcium ions inside the cell and cause inhibition in reply to cAMP. Although these receptors are classed into the same family they tend to have very different amino acid sequences, with relatively very few points of homology between them. The most predominant receptors in the hypothalamus are the Y1, Y2, Y4 and Y5 and it is these which are believed to play a role in energy homeostasis.

The Y1 and Y5 receptors are involved with orexigenic effects. Y1 receptor mRNA was found to be expressed in the PVN and ARC of the hypothalamus. In rats it has been shown that injection of a Y1 antagonist into the hypothalamic region caused suppression of feeding which suggests a role of the Y1 receptor as a mediator for spontaneous feeding. Further backing this up is that in genetically obese ob/ob mice which have had their Y1 receptors there was observed a decrease in body weight [xxxv] .

The Y5 receptor