الفهرس 
INTRODUCTION AND AIM OF WORKOnly 14 pages are availabe for public view
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Abstract
SUMMARY AND CONCLUSION Hyperphagia (overeating) is often associated with energy over storage and obesity, which may lead to a myriad of serious health problems, including heart disease, hypertension, and type II diabetes mellitus. Thus understanding the complex pathological mechanisms underling hyperphagia and obesity has important clinical significance. Fasting therapy was at first mainly used for the treatment of obesity. The precise mechanism(s) underlying the physiological changes during fasting remains unclear; however, there is indirect evidence that such an effect may be mediated by alterations in the hypothalamic-pituitary-adrenal (HPA) axis, insulin and/or metabolic and energy homeostasis. Clarifying the underlying mechanisms will be essential to understanding the pathogenesis and treatment of energy balance disorders, such as obesity which is a major health problem and cachexia such as cancer cachexia and cachexia associated with inflammatory bowel diseases The hypothalamus regulates many aspects of energy homeostasis, adjusting the drive to eat and the expenditure of energy in response to a wide range of nutritional and other signals. Orexins, also named hypocretins, are neuropeptides present in the hypothalamus. Prepro-orexin is enzymatically matured into two peptides, orexin-A and orexin-B which are 33-and 28-amino-acid peptides, respectively. The orexin signaling pathway thought to participate in a complex cycle of energy homeostasis, including control of food intake, wakefulness, motor activity, metabolic rate, cardiovascular and endocrine effects. However, the role of orexins in energy expenditure is more prominent than in food intake. Many studies have extended the multifaceted role of orexins to the regulation of peripheral functions either through a central control or direct interaction with peripheral target tissues such as hypophysis, adrenals, GIT or endocrine pancreas. In a trial to clarify the possible effects of orexin-A on insulin secretion, the hypothalamo-pituitary-adrenal axis function, and the adrenergic system, as regulators of energy homeostasis, this study had been carried out on a total number of 60 adult male albino rats. The animals were divided into 3 equal groups and each group is subdivided into two equal subgroups: one for measurement of (serum insulin, blood glucose, serum corticosterone, and ACTH) and the other for measurement of the adrenergic system parameters (arterial blood pressure, H.R, and urinary VMA excretion/24 hour). Group I Control group: saline vehicle treated group. Group II Each rat was given daily S.C injection of orexin–A (20 nmol/ Kg body weight) dissolved in 0.2 ml 0.9% Na Cl for 7 days . Group III Each rat was given daily S.C injection of orexin–A (20 nmol/ Kg body weight) dissolved in 0.2 ml 0.9% Na Cl for 14 days. The results of this study show that, orexin-A was effective in stimulating insulin release in vivo and participated in long term regulation of insulin secretion. Nevertheless, from this study, it is not known whether orexin-A increases insulin release by acting directly on the pancreatic ?-cells or via an indirect pathway. Insulin is known as a long-term regulator of food intake and energy balance. Moreover, some studies demonstrated that, orexin-A plays an important role in the adipo-insular axis by stimulating insulin and leptin secretions. Taken together, the findings of this work may be indicative of a therapeutic role of orexin–A in the treatment of obesity and associated diabetes on both of the short and long term. This work also shows that, orexin-A was effective in stimulating corticosterone release in vivo and participated in both short term and long term regulation of corticosterone by acting directly on the adrenal glands, as there was an insignificant change in the levels of ACTH in the plasma after the administration of the drug for 7 days. Furthermore, a significant decrease in its plasma levels was detected after 14 days of orexin-A administration, which resulted from the negative feed back inhibition exerted by the long term elevated corticosterone levels. Therefore, orexin-A might be involved in the patho-physiology of adrenal function. Moreover, as both the orexinergic system and the HPA axis are activated in stress conditions, so they may interact to regulate energy homeostasis during stress conditions and orexin-A may mediate these stress responses improving response to stress in daily life. The results of this work also demonstrated that, orexin-A was effective in stimulating the adrenergic system which evidenced by the significant increase in the cardiovascular activities (blood pressure, heart rate) and the levels of urinary VMA/24 hours after the administration of the drug for 7 days. However, these measured parameters returned to the control levels after 14 days of orexin-A administration, and so, these results indicate that, orexin-A may participate in short term but not in long term regulation of the adrenergic system. Nevertheless, from this study, it is not known whether orexin-A acting centrally at the higher levels or directly on the adrenal medulla to exert this effect. Finally, narcolepsy which is tightly associated with orexin-A deficiency, was reported to be associated with changes in energy homeostasis, as narcoleptic patients are frequently obese, more often have insulin resistant diabetes, exhibit reduced food intake, and have lower blood pressure and temperature and this deficiency is directly involved in altered energy homeostasis in those patients. Thus, this pleuripotent orexin-A peptide hold great potential not only for the treatment of narcolepsy but also to provide insight into the coordinated regulation of multiple systems affected in this disorder .Furthermore, pharmacological intervention directed at the orexin receptors may prove to be an attractive avenue toward the discovery of novel therapeutics for diseases involving dysregulation of energy homeostasis such as obesity and diabetes mellitus. Fasting therapy was at first mainly used for the treatment of obesity (1) and since the 1970s this therapy has also been found to be one of the effective treatments for psychosomatic disorders (2). The precise mechanism(s) underlying the psychological and physiological changes during fasting remains unclear; however, there is indirect evidence that such an effect may be mediated by alterations in the hypothalamic± pituitary±adrenal (HPA) axis and/or metabolic and energy homeostasis (3±5), as indicated in acute mental and environmental stresses (6, 7). Recently, peptides such as orexin, neuropeptide Y (NPY) and leptin have been found to play an important role in the regulation of energy metabolism (8±10). The mechanisms by which they interact with each other (11±13) and with other nutritional and metabolic factors including insulin and cortisol (8, 14) have been investigated in animals. In humans, on the other
hand, the changes in circulating levels of leptin and NPY in response to various nutritional states such as fasting (15±17) and to psychological and/or physical stresses (18±20) were studied; however, changes in orexin concentrations have not yet been investigated. Interestingly, orexin-containing neurones were recently found in the gut that expressed a functional change in response to energy status (21). Although changes in circulating levels of these peptides in the periphery in response to fasting cannot be assumed to have any relationship to those in the central nervous system, it seems important to investigate if these peptides are of
physiological importance and how they are regulated in the periphery during fasting in humans Hypocretinergic neurons may regulate sympathetic and cardiovascular activity. Furthermore, their antagonists may apply for the treatment of hypertension and cardiovascular diseases in the future. Shirasaka et al.,2003). The concept of the hypothalamus playing a role in the regulation of feeding behavior and energy homeostasis was originally based on observations of brain lesions (Oomura, 1980). Lesions of the ventromedial hypothalamus (VMH) produce hyperphagic obesity, whereas lesions of the lateral hypothalamus (LH) induce hypophagia and weight loss, suggesting that satiety and feeding centres existed in the VMH and LH, respectively(Bernardis and Bellinger, Orexins, also named hypocretins, are neuropeptides present in hypothalamic neurons were discovered in 1998 by subtractive cDNA cloning or orphan receptor technologies. Prepro-orexin is enzymatically matured into two peptides, orexin-A and orexin-B which are 33- and 28-amino-acid peptides, respectively. Two cloned orexin receptors OX1R and OX2R are serpentine G-protein- coupled receptors, both of which bind orexins and are coupled to Ca2+ mobilization.(Sakurai et al.,1988) Orexins are neuropeptides present in hypothalamic neurons that project throughout the central nervous system to nuclei involved in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis and autonomic regulation. (Pyron et al.,1998) The interest of investigators in orexins has focused on narcolepsy , since genetic or experimental alterations of the orexin system are associated with this sleep disorder. However, orexins are not restricted to the hypothalamus and together with their receptors they are expressed in peripheral tissues.(Hungs and Mignot, 2001). The expression of orexins and/or orexin receptors in several peripheral rat tissues suggests a more widespread action of orexins at the periphery in Endocrine pancreas testis, kidney, heart, thyroid and lung [Nowak et al.,2000, 75 Further studies indicate more complex array of orexins functions and effects. The orexin signaling pathway thought to participate in a complex cycle of energy homeostasis , including control of food intake motor activity , metabolic rate, heart rate, and blood pressure.(Preti , 2002). insulin is known as a long-term regulator of food intake and energy balance, orexins play an important role in the adipo-insular axis by stimulating insulin and leptin secretions [Jaszberenyi et al.,2001] orexin-A was also effective in stimulating insulin release in vivo(Irahara et al.,2001) and in an in vitro perfusion system (Nowak et al. ,2000). Nevertheless, from these studies, it is not known whether orexin-A increases insulin release by acting directly on the ?-cells or not (Kirchgessner , 2002). Many lines of evidence indicate that close interrelationships occur between body weight homeostasis and adrenal secretory activity , However, Several lines of evidence suggest that orexins influence neuroendocrine homeostasis and modulate hormone secretions in the hypothalamo-pituitary-adrenal axis (HPA) (Viosin et al.,2003). As both the orexinergic system and the HPA axis are activated in stress conditions , so they may interact to regulate energy homeostasis during stress conditions. Orexin containing fibres project widely to the CNS , and orexin receptors have been found in areas known to participate in the control of the autonomic nervous system(Preti,(2002).Also, Very recent reports indicate that (i) orexin-containing neurons of the lateral hypothalamus project to brown adipose tissue [Nakamura et al.,2000] .Hypocretinergic neurons may regulate sympathetic and cardiovascular activity. Furthermore, their antagonists may apply for the treatment of hypertension and cardiovascular diseases in the future. Further stdies are needed to better understand the signal transduction pathways of orexin receptors; (iv) to evaluate the involvement of orexins in other peripheral functions; (v) to understand the physiological role, if any, of circulating orexin and its site(s) of origin, i. e. gastrointestinal tract or other sources, and (vi to explore peripheral tissue functions in orexin or orexin receptor knock out mice. Following such studies, orexins will likely be promoted as major regulatory peptides.