One of the greatest problems confronting modem society is obesity. Obesity is a recognized health problem which is associated with cardiovascular disease, diabetes and certain forms of cancer. Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia. Obesity is also a risk factor for the group of conditions called insulin resistance syndrome. Carrying extra body weight and body fat go hand and hand with the development of diabetes. Diabetes mellitus is a hormone disorder which afflicts millions of people annually. It is characterized by an inability to maintain homeostasis of glucose in the bloodstream. Thus the primary symptom of acute diabetes is hyperglycemia. A secondary set of symptoms arises in chronic or long-standing diabetes. These include degeneration of the walls of blood vessels, causing serious vascular complications involving both macro- and microvessels. People who are overweight are at a much greater risk of developing type 2 diabetes than normal weight individuals. Almost 90% of people with type 2 diabetes are overweight. Effective weight management for individuals and groups at risk of developing obesity involves a range of long term strategies. These include prevention, weight maintenance, management of co-morbidities and weight loss. Existing treatment strategies include caloric restriction programs, surgery (gastric stapling) and drug intervention. The currently available anti-obesity drugs can be divided into two classes: central acting and peripheral acting.
Many factors may predispose a person to excessive body fat. These include: eating patterns, environment, psychological factors such as body image, and biochemical differences related to resting metabolic rate, dietary-induced thermogenesis, levels of spontaneous activity, basal temperature, levels of cellular adenosine triphosphatase, lipoprotein lipase and other enzymes, and metabolically active brown adipose tissue. Obesity most commonly arises as a result of the imbalance of caloric intake and caloric expenditure. However, the propensity to become obese may be affected by certain genes and, in addition, certain metabolic disorders have a direct effect on weight gain, for example, growth hormone deficiency or hypothyroidism. Regardless of the underlying physiological cause of obesity, appetite regulation is a key factor in controlling weight gain and maintenance of body weight. Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Among the many possible solutions for treating obesity are formulations of weight loss products that work with some of the basic biochemical processes involved in fat metabolism. This process has been exploited through pharmaceutical intervention at the neurocrine level as well as at the level of fat cells themselves, or the way fat cells metabolize fats in brown adipose tissue. Thermogenisis is the process whereby food intake is converted to body heat through the metabolic process of caloric conversion. In obese people, certain metabolic defects associated with the thermogenic process begin to appear. These metabolic predispositions manifest in a number of identifiable biochemical syndromes that can be attacked through therapeutic intervention with agents that over-ride the cascade of events leading to obesity. One of the more natural approaches to starting artificial thermogenisis, that is, thermogenisis that is unrelated to food consumption, is the use of plant derived substances that contain ephredine or ephedrine like compounds such as ma-haung or ephedra. Ephedra (Ma Huang) is an herb that grows wild in parts of the western United States. Ephedra contains ephedrine, an alkaloid that stimulates the production of catecholamines such as norepinephrine. Norepinephrine or noradrenaline is presumed to start the thermogenic process by stimulating metabolism in fat cells via the neurocrine axis that involves beta-adrenergic receptors. This in turn results in lipolysis, or the liberation of fat in fat cells via an increase in the basal metabolic rate.
Obese people tend to have low basal levels of growth hormone (GH) and fail to secrete significant amounts of GH in response to a variety of stimuli, including growth hormone releasing hormone (GHRH). Growth hormone releasing factor (GRF), also called growth hormone releasing hormone (GHRH), is a 44 amino acid peptide of the glucagon-VIP-PHI family and is present in high concentration in the hypothalamus, particularly in the arcuate nucleus and medium eminence. GRF is the primary stimulatory factor controlling synthesis and secretion of pituitary growth hormone (GH), a critical regulatory hormone of metabolic homeostasis controlling breakdown of fat (lipolysis) and synthesis of protein. Thus a normal level of GRF is required for appropriate levels of GH to maintain muscle mass while promoting lipolysis. Growth hormone is known to accelerate lipolysis in normal and obese humans. It is now clear that neural and hormonal systems interact at virtually every step in feeding satiety and metabolic control. Central to this new understanding has been the recognition of the roles subserved by key neural systems operating within the brain, specifically within the hypothalamus. Of the many systems acting within the hypothalamus to regulate appetite and metabolism is neuropeptide Y (NPY) which is now recognized to play a pivotal role. NPY is a 36-amino acid peptide and is the most abundant neuropeptide to be identified in mammalian brain. NPY is an important regulator in both the central and peripheral nervous systems and influences a diverse range of physiological parameters, including effects on psychomotor activity, food intake, central endocrine secretion, and vasoactivity in the cardiovascular system. The relationship between hypothalamic levels of growth hormone releasing factor (GRF) and food deprivation is the opposite of that observed with NPY. Specifically, levels of GRF are reduced in the hypothalamus following food deprivation. Growth hormone plays an important role in the regulation of somatic growth and metabolism. The metabolic effects of human growth hormone (HGH) have been divided into early insulin-like effects, associated with enhanced glucose utilization and increased amino acid transport, and into anti-insulin-like effects, associated with the stimulation of lipolysis and depression of glucose utilization. GH promotes nitrogen conservation. Obese people have a blunted or suppressed growth hormon release, even when subjected to growth hormone injections or other nutritional components that have an effect on growth hormone release in normal healthy subjects. Obesity impairs the release of growth hormone from the pituitary gland. This problem is of particular importance in obese children whose growth may be impaired. It is fully reversible if weight is lost.
Growth hormone is a polypeptide hormone synthesized in and secreted by the adenohypophysis. Growth hormone is synthesized as a precursor protein containing an N-terminal signal peptide and the growth hormone sequence. Growth hormone is normally produced throughout life, although in highest amounts during the pre-adult period. The hormone is required for pre-adult growth. Growth hormone is known to promote skeletal growth, nitrogen retention, protein synthesis and affects glucose and lipid metabolism. In other words, growth hormone is a general anabolic agent. Human growth hormone has been implicated in a number of metabolic effects. Administration of exogenous growth hormone by injection has been shown to accelerate body fat loss, and produce anabolic effects in obese human subjects. It has also been shown that human growth hormone (hGH) in human beings, acts as a potent regulator of body fat storage, and thus promotes breakdown of adipose tissue in obese humans while preserving lean tissues. Growth hormone secretion is regulated by two hypothalamic neurohormones; growth hormone releasing hormone (GHRH) and somatostatin (SRIH). GHRH stimulates growth hormone while SRIH has a inhibiting influence. Insulin like growth factor I (IGF-1), mediates the biological actions of growth hormone through negative feedback. A number of nutritional, dietary, and metabolic factors influence the growth hormone-insulin-like growth factor (GH-IGF I) interaction. Insulin levels are elevated in obesity, and high insulin levels also suppress growth hormone production. Obese people have high levels of circulating free fatty acids (FFA), and free fatty acids have been shown to suppress growth hormone release. High free fatty acids at night inhibit growth hormone production, particularly in obese people, and obese subjects have higher levels of circulating free fatty acids than non-obese subjects. Furthermore, catecholamines such as noradrenaline, stimulate free fatty acid release which inhibits lipolysis in adipose or fat cells. Compounds such as ephedra stimulate catecholamine production during thermogenisis, which in turn elevates free fatty acids. Plasma free fatty acids and triglycerides can be reduced by oral administration of nicotinic acid, or esters, analogues. |
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