PYY,THE ANTI GHRELIN HORMONE: BECOME A PROMISING TARGET IN OBESITY THERAPY

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Abstract:

Obesity is one of the greatest threats to the health of the developed world. In order to design effective drugs to treat the alarming increase in obesity, it is essential to understand the physiology of normal appetite control and the pathophysiology of obesity. This obesity epidemic is caused by both biological and environmental factors. The environmental factors include the over consumption of food due to its increased availability, lower prices, high calorie density and good taste. In addition the trend towards a less active lifestyle results in the reduction of energy expenditure.
Recent evidence suggests that certain gut hormones – ghrelin, Peptide YY3-36 (PYY(3-36)) , pancreatic polypeptide, glucagon-like-peptide 1, cholecystokinin (CCK) and oxyntomodulin,– have a physiological role in governing satiety via the hypothalamus.Gut hormone appetite-regulatory systems represent a potential target for the design of antiobesity drugs.2 A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3–36) might have a chance of achieving sustained weight loss.
The hormone, PYY (for peptide YY 3-36), is of particular interest because it appears to be the intestine's signal of satiety and because overweight people normally make less of it than thin people.12 It is the anti-ghrelin because this hormone makes one feel full. The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH).16 PYY inhibits Neuropeptide Y and Agouti-related peptide, leading to a lower appetite because these molecules increase appetite and decrease metabolism.3-5. Peripheral administration of full length PYY increase fluid and electrolyte absorption from ileum and inhibit gut motility, meal induced pancreatic and gastric secretion, and emptying8-9. It also act as a vasoconstrictor. The action of peripheral PYY 3-36 on satiety appear to be mediated by a direct action on the accurate Y2 receptor, a presynaptic inhibitory receptor of neuropeptideY neurone.2 PYY released postprandially in proportion to the amount of calories ingested 17 .

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Introduction :
The 1999 - 2000 National Health and Nutrition Examination Survey (NHANES) showed that nearly 65% of adults in US are overweight, 31% of those obese. The World Health Organization (WHO) reports that being overweight is one of the top 10 risk conditions in the world - the top 5 in developed countries. Obesity increases the risk for type II diabetes, heart attacks, stroke and some cancers.3-5
The World Health Organization has classified obesity as an epidemic, and the associated healthcare costs pose a vast financial burden.17 Adult definitions of overweight and obesity use body mass index (BMI) cut-off points of 25 and 30 kg/m2 related to long term adverse outcomes. The prevalence of obesity in adults has increased by over 75% worldwide since 1980.18 The definition of obesity in children is complex as endpoints of mortality and disease are less common. The current definition is based on age and gender specific 85th and 95th centiles of BMI. Around 22 million children under 5 worldwide are obese,19 and in the UK the prevalence of childhood obesity rose from 1.2% in 1984 to 6% in 2002–03.20
Peptide YY is a 36-amino-acid hormone synthesized primarily in L-type enteroendocrine cells in the colon and ileum and in cells along the periphery of pancreatic islets. Like that of other gastrointestinal hormones, release of peptide YY appears to be stimulated by the presence of enteral secretagogues, especially dietary fat, present in the distal intestine.6PYY 3–36 appears to inhibit appetite by acting directly on the Y2 receptor in the ARC—a presynaptic inhibitory autoreceptor.Although there has been variability in reproducing the anorectic effects of PYY 3–36 in rodents, this may be due to the confounding effects of stress, which can itself reduce food intake via the arcuate nucleus.21Basal plasma PYY levels were higher in ad libitum-fed pigs than in fasted pigs suggesting that circulating PYY(3-36) levels influence satiety and contribute to the termination of feed intake in pigs.15The decreases in appetite only occurred during meals early in the day. However, PYY did not affect food intake in the evening. In addition, high doses of PYY are required to cause weight loss10.
PYY itself, because, as a naturally occurring molecule, it might not be patentable. A new molecule related to PYY would be patentable1. While it is an interesting potential anti-obesity target, creating a pill would be difficult because it is a small protein that will be digested before it has an opportunity to exert its action.However, it may be possible to find non-protein activators of the PYY 3-36 receptor.
Delivery system of PYY :
1. Appetite Control Nasal Spray made by a company called Nastech. This is an upcoming prescription drug product still in Phase II testing that could someday offer tremendous potential to help people lose weight.The promise is that by inhaling this protein,appetite will be reduced.13
2. Emisphere's eligen(R) technology has enabled the oral delivery of PYY. With Emisphere's delivery agent PYY can orally deliver as a single tablet. It significantly reduce Ghrelin levels in healthy male subjects. Emisphere's business strategy is to develop oral forms of injectable drugs, either alone or with corporate partners, by applying its proprietary eligen(R) technology.22
Side effect :
PYY might act on the cardiovascular system and gut in large doses could theoretically affect heart rate and blood pressure or cause digestive problems like diarrhea1.
Conclusion :
Strategies available for the management of obesity include appetite inhibition, reduction in nutrient absorption, increase in energy expenditure, and alteration of fat distribution. Many treatments are effective in the short term, but long term efficacy in maintaining weight loss is crucial. Two classes of anti-obesity drug are currently available in the UK. One class inhibits pancreatic lipase and reduces fat absorption like Orlistat. But it has several gastrointestinal side effects and is only licensed for use for a period of two years at present. The other class of drugs acts centrally to suppress appetite. This group includes sibutramine, use of which is restricted to one year. It has several side effects, particularly tachycardia and hypertension.17
PYY 3-36, is made in the colon and also inhibits food intake. When it is infused in people, it produces a long-lasting and profound reduction in food intake.In a study, whose results appear in The New England Journal of Medicine, 24 volunteers, half of them overweight and half of them lean, received PYY or a saltwater placebo at 8:30 a.m. An hour and a half later, they were ushered in to a buffet lunch. On average, those who had received PYY ate 30 percent less.12 As PYY is a naturally occurring molecule and have not any serious toxic effects so it can use as a antiobesity target for long term use. Obese subjects have a lower fasting basal PYY and a diminished postprandial rise, but remain sensitive to the inhibitory effects on appetite following exogenous administration. Thus PYY 3–36 might constitute a candidate target for anti-obesity therapy.23
Reference :
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