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FAT ATTACK MARCH 05

Posted by: Unknown توقيت نشر: 18:13 / comment : 0 , , , , ,

Excess Pounds By Dropping a Load

A Glycemic Load

            Bodybuilders fret and worry about every last ounce of fat as they prepare for a contest. For those grueling eight to 12 weeks, calories are counted and carbohydrates are cut in the effort to reach an extremely low body fat. Once the stage lights dim, the temptation for an ice cream sundae may become overwhelming and pizza lures erstwhile athletes back into the comfortable zone of complacency with its siren song of sauce and toppings.
            With the exception of a rare few, most athletes, bodybuilders and celebrities relax their standards, gaining several pounds during their off-season. After the first few weeks to months, the added girth becomes uncomfortable and unpleasant by their standards, causing them to actively begin managing their weight again through a moderate diet plan.
            Everyone, even the larger-than-life celebrities created by sports and the media, worries about gaining excess weight. In addition to the pressure of being in the spotlight and the career need to look good, every person- public and private- has to consider the impact of extra fat on future health. Longevity and health are taken for granted by teenagers and young adults, but once issues like home ownership and teacher conferences become more important than music videos and all-night raves, it's time to pay attention to health maintenance. Suddenly, the day will come when headlines about heart health and cancer prevention are as eye-catching as Ronnie Coleman's biceps workout or a Halo 2 review.

            Why Low-Fat Diets Don't Succeed
The basics of losing weight are simple; take in fewer calories than you burn.1 For athletes, it's more important to lose fat than weight, but the essentials are very similar. For years, dieticians had nice, long tables they could proudly display showing the calorie content of every food product. To add credence to their technique, they often teamed up with a health organization, like the American Heart Association, claiming their method would improve health and prolong the life span.2 The doctrine for years was to eat a low-fat diet, as the evil saturated fats that dripped from T-bone steaks and cheeseburgers would clog arteries and deposit squarely, (actually roundly, unless you are a yellow sponge), on your hips.
            Yet, as we have learned thanks to pioneers like Barry Sears and Robert Atkins, the traditional low-fat diet is no safer than other alternatives. In fact, low-carb/high-protein diets like the Zone and South Beach have been shown to be more effective in the short term and possibly even healthier alternatives than the carbohydrate- dominant, low-fat diets touted by dieticians and cardiologists.3-6
            In the search for an explanation for the relative failure of low-fat diets in facilitating weight loss and improving health, scientists have identified a likely culprit: refined carbohydrates.7 As the less well regarded high-protein diets have explained, to maximally promote fat loss, the release of insulin must be controlled.8 Insulin is a hormone produced by the pancreas, a gland located in the belly. When the body detects a rise in blood sugar, insulin is released and travels through the bloodstream. Insulin interacts with receptors on most cells and tissues in the body, the brain being the primary exception, starting a signal that drives sugar from the blood into active tissues, such as muscle.9,10
In addition to its action on blood sugar, insulin affects fat metabolism. When insulin is elevated, or if it remains elevated above normal fasting levels, fat cells are encouraged to store fat and are inhibited from releasing any stored fat.10,11 Other negative changes are also associated with persistently high insulin levels, including high triglycerides, low HDL (good cholesterol), high blood pressure, central (abdominal) obesity, increased risk of blood clots and chronic inflammation.10,12 This collection of problems is termed the metabolic syndrome and is being recognized as one of the greatest health threats facing the nation's health care system.13
           
            The Insulin Connection
Obviously, there are notable reasons to control insulin. Most people who are aware of insulin have a rough idea of how to manage it- by cutting down sugar in the diet. This basic level of understanding is an excellent start. Refined carbohydrates, whether they come from candy, bread, potatoes or pastries, flood the system with sugar and a vigorous insulin response is required to deal with the sugar tsunami.14,15 The insulin peak can remain elevated, even after the sugar levels have fallen back to normal. This accounts for the sudden lethargy that is experienced after a sugar rush, sometimes called an insulin dump.
 In some people, often sedentary individuals who tend to be overweight, the body becomes resistant to insulin's signal and greater amounts of insulin are released for longer periods.13,15 The persistence of elevated insulin is a condition that precedes the metabolic syndrome. Some researchers believe insulin resistance is not just a component of the metabolic syndrome, but is actually the cause of the condition.10,12,16
            Dieticians recognize that the body does not respond to all carbohydrates in the same fashion. Simple sugars elicit a vigorous insulin response, but others induce a more mild insulin response. The insulin response appears to be related to the rate at which sugars from food are digested and absorbed into the bloodstream. Foods that quickly release sugar into the bloodstream cause a fast and large peak in insulin levels; such foods rate high on a scale called the glycemic index.14,15 Thus, sugary foods like kids' cereals, white bread and many sports drinks are called "high glycemic index foods." Carbohydrates that break down slowly, like whole grains and beans, release sugar into the system slowly and stimulate a mild insulin response; these are "low glycemic index foods."
Beyond the concept of the glycemic index is a calculation called the glycemic load. The glycemic load of a diet is calculated by multiplying the glycemic index of a diet by the number of carbohydrates (in grams). The practice behind many of today's popular diets is to lower weight and improve health by decreasing the amount of insulin released. Researchers recently published a study comparing a low glycemic load diet to a traditional low-fat diet relying upon breads and other high glycemic index foods on weight loss, metabolism and heart disease risk factors.17

            New Research
In this study, two groups of overweight individuals were subjected to baseline measurements and then given prepared meals designed to induce weight loss by providing only 60 percent of calculated maintenance calories. The subjects were required to show up every day to eat the prepared lunch under the observation of the researchers; then they were provided with a prepared snack, dinner and breakfast to eat off-site with instructions not to eat any outside foods. After subjects reached a target weight loss of 10 percent of initial bodyweight, they were re-measured and comparisons were made between the two groups.
            The first measure of note was the effect of the different diets on blood sugar and insulin. As intended, after eating the prepared meals, blood sugar and insulin was twice as high in the group following the traditional low-fat diet. While the low glycemic load subjects reached target weight quicker, both groups took on average slightly over two months to lose 10 percent of their initial bodyweight. Neither group demonstrated an advantage in maintaining or developing lean mass during weight loss, but this is not surprising, as exercise was not part of the weight loss program.18
            On the surface, it would appear there's no added benefit to controlling glycemic load, other than slightly quicker results. Bear in mind, these groups consisted of people who were not athletes, let alone bodybuilders. However, when examining the effect of the two diets through blood analysis and metabolic studies, the potential health benefits of lowering the glycemic load of the diet become evident. Perhaps, it might be more forceful to say the potential health risks of the traditional low-fat diet are exposed.
            Resting energy expenditure is a term used to describe the basal metabolic rate, or how many calories are burned at rest. Weight loss generally has a negative effect on resting energy expenditure, meaning it becomes more difficult to lose more weight because the body is trying to protect itself from starvation by burning fewer calories at rest. Though both groups demonstrated a drop in resting energy expenditure, the degree of reduction was twice as great for the traditional low-fat diet group (176 vs. 96 calories per day). This means the low-fat group burned fewer calories every day, increasing the likelihood of regaining weight and making it more difficult to maintain weight loss. Eighty calories per day does not sound like much, but it's the caloric equivalent of walking one mile. All else being equal, the low glycemic load diet would allow for the loss of an additional eight pounds per year, every year.
Avoiding wild swings in insulin and blood sugar also seem to help control hunger, as subjects from the low glycemic load group reported being less hungry.

            Important Discoveries
Blood analysis revealed some very important discoveries that could impact individual health and the health care system in general. As discussed earlier, insulin resistance is one of the early signs preceding the onset of the metabolic syndrome. Using a scale that measures insulin resistance, it was shown that while the low-fat group improved significantly, the degree of improvement was two times higher in the low glycemic load group.
            As would be expected using the metabolic syndrome model, as insulin resistance decreased, improvements were seen in nearly all the associated signs and symptoms. Serum triglycerides, fats that float in the bloodstream affecting the risk of vascular disease, were significantly lower in the low glycemic load group. While cholesterol values were not significantly different between the two groups, a dramatic effect was noted on the state of inflammation. Inflammation in the vascular system is believed to be the initiating event in blood clots that lead to strokes and heart attacks.19
Only recently has the importance of lowering vascular inflammation been recognized. This inflammation is measured by levels of a marker called C-reactive protein. In the low glycemic load group, C-reactive protein decreased by 50 percent, while it remained unchanged in the low-fat group. This revelation alone is sufficient reason to recommend lowering the glycemic load of the diet. Lastly, blood pressure was reduced to a greater extent in the low glycemic group, though the change was not significant. This may be a factor of the relatively few subjects in the study.
            It is amazing that the dogma of the established "experts" is constantly failing the scrutiny and challenge of close examination; yet, the dietary practices of bodybuilders are standing up to objective criticism by scientists. Despite the growing body of evidence supporting the experiences and recommendations that have been gained over the decades by dedicated and disciplined athletes, the media and many regulatory agencies continue to dispute the efficacy of the bodybuilding lifestyle.4,5 Whether this is due to professional pride, political influence or a media agenda, it is unfortunate. The public has been conditioned to scoff at the minority that considers physical development to be part of a well balanced life and suffers because it is being misled about issues that impact everyone at both an individual and societal level.20 As this study clearly shows, the old guard is not infallible and it is time to embrace new ideas. 

References 

  1. Finer N. Low-calorie diets and sustained weight loss. Obes Res, 2001 Nov;9 Suppl 4:290S-294S.
  2. Bunyard LB, Dennis KE, et al. Dietary intake and changes in lipoprotein lipids in obese, postmenopausal women placed on an American Heart Association Step 1 diet. J Am Diet Assoc, 2002 Jan;102(1):52-7.
  3. Yancy WS, Olsen MK, et al. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med, 2004 May 18;140(10):768-77.
  4. Astrup A, Meinert Larsen T, et al. Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss? Lancet, 2004 Sep 4;364(9437):897-9.
  5. Acheson KJ. Carbohydrate and weight control: where do we stand? Curr Opin Clin Nutr Metab, Care 2004 Jul;7(4):485-92.
  6. Foster GD, Wyatt HR, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med, 2003 May 22;348(21):2082-90.
  7. Schulze MB, Manson JE, et al. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA, 2004 Aug 25;292(8):927-34.
  8. McLaughlin T, Abbasi F, et al. Relationship between insulin resistance, weight loss, and coronary heart disease risk in healthy, obese women. Metabolism, 2001 Jul;50(7):795-800.
  9. Rosenfeld L. Insulin: discovery and controversy. Clin Chem, 2002 Dec;48(12):2270-88.
  10. Ferrannini E, Galvan AQ, et al. Insulin: new roles for an ancient hormone. Eur J Clin Invest ,1999 Oct;29(10):842-52.
  11. Jacob S, Hauer B, et al. Lipolysis in skeletal muscle is rapidly regulated by low physiological doses of insulin. Diabetologia, 1999 Oct;42(10):1171-4.
  12. Deskalopolou SS, Mikhailidis DP, et al. Prevention and treatment of the metabolic syndrome. Angiology2004 Nov-Dec;55(6):589-612.
  13. Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology, 2003 Dec;144(12):5159-65.
  14. Morris KL, Zemel MB. Glycemic index, cardiovascular disease, and obesity. Nutr Rev, 1999 Sep;57(9 Pt 1):273-6.
  15. Pewlak DB, Ebbeling CB, et al. Should obese patients be counseled to follow a low-glycemic index diet? Yes.Obes Rev, 2002 Nov;3(4):235-43.
  16. Harris NS, Winter WE. The chemical pathology of insulin resistance and the metabolic syndrome. Med Lab Obs, 2004 Oct;36(10):20-25.
  17. Pereira MA, Swain J, et al. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA, 2004 Nov 24;292(20):2482-90.
  18. Tsai AC, Sandretto A, et al. Dieting is more effective in reducing weight but exercise is more effective in reducing fat during the early phase of a weight-reducing program in healthy humans. J Nutr Biochem, 2003 Sep;14(9):541-9.
  19. Kaplan RC, Frishman WH. Systemic inflammation as a cardiovascular disease risk factor and as a potential target for drug therapy. Heart Dis, 2001 Sep-Oct;3(5):326-32.
  20. Kruger J, Galuska DA, et al. Attempting to lose weight: specific practices among U.S. adults. Am J Prev Med,2004 Jun;26(5):402-6.

FAT ATTACK JAN 18

Posted by: Unknown توقيت نشر: 18:12 / comment : 0 , , , , ,

OEA: How Your Gut Says "Enough is Enough"

Obesity has increasingly become a health crisis, causing lives to be shortened and medical care costs to skyrocket. Surprisingly, the government and media have demonized supplements and over-the-counter weight loss products. Two effective weight loss ingredients, phenylpropanolamine (PPA, previously found in Dexatrim) and ephedrine (the active ingredient in ephedra-based supplements), have been removed from the market due to reported adverse side effects.1,2 The case against PPA has been criticized and appears to be insufficient for the action, particularly when one argument was that obesity is not a pressing concern to American health care.3Ephedrine has been associated with serious consequences, including death, though many of the cases involved abuse of the herbals for its stimulant effect or use by people with pre-existing disease or poor physical condition.4

Society of Gluttons
So, as the problem of obesity increases and the treatment options decrease, researchers scramble to discover the hormones or chemicals that may safely aid in weight control. One trend that has appeared over the last decade is the understanding that the body has multiple routes of sensing and communicating food consumption and energy stores. Recently discovered hormones, such as leptin and ghrelin, have become familiar to the general public as media attention has focused on the obesity issue. Pharmaceutical companies, recognizing the financial potential of this market, are sponsoring research and filing patents, hoping to capitalize on the next promising discovery.
Obesity treatment is always of interest to bodybuilders, as fat loss is as important to stage appearance as muscularity. Bodybuilders struggle with fat as much as the obese, though at different extremes of the body fat scale. Bodybuilders have five to seven meals a day following an unending urge to gain size. Yet, when the pre-contest phase of training begins, the diet is reduced to catabolic levels. Competitive bodybuilders experience six to 12 weeks of constant hunger and often succumb to binge eating and bizarre cravings. Listening to the rumble of an empty stomach, most would give a week's paycheck just to feel full.
Fullness is a wonderful feeling, taking away the pressure of hunger and allowing the relaxation of a well-fed state. Fullness can provide the strength to resist snacks, overly large portions and the dreaded lure of the fast food drive-through. Unfortunately, until recently, the only way to feel full was to eat. However, science has progressed to the point that nearly every action and process is being defined at the molecular level. As mentioned earlier, the body is a system that is in constant communication. Every time there's a change in the environment, signals are sent back and forth, via neurotransmitters and hormones, affecting the behavior and function of the body.
Eating and energy stores are closely monitored, and in normal settings, maintain an even balance between necessary fat stores and the drive to eat more. However, western society has changed living conditions faster than evolution or adaptation can adjust. Refrigeration, buffets and refined sugar, in addition to other factors, have combined to create a society of gluttons. Now, it's necessary to turn to science to restore the signals and balance that nature has provided to maintain a minimal level of health.

            The Marajuana Connection
In 2001, a report was published in the prestigious science journal Nature about the discovery of a fatty acid ethanolamide that signals satiety (a feeling of fullness).5 This fatty acid ethanolamide is a naturally occurring chemical found in the membrane of animal and plant cells, called oleylethanolamide (OEA).6,7 The effects of OEA were first studied because of the chemical similarity to another chemical, a cannabinoid known as anandamide.8
The classification of anandamide as a cannabinoid should give some clue as to its origins and function in appetite control. Cannabinoids are chemicals found in the plant Cannabis sativa, also known as marijuana. Among users of marijuana, it's commonly reported that smoking the leaves of the plant causes an increased desire to snack, or as it is referred to in popular culture, "the munchies." This hunger is likely due to the effect of the chemical anandamide, which occupies specific cannabinoid receptors, subsequently changing the person's behavior by triggering a feeding response.9
OEA has a chemical structure that is similar to anandamide, so investigators studied its effects on eating and weight management.5  OEA was found to have the opposite effect of anandamide, decreasing hunger and reducing both food intake and body weight.5 Researchers further studied OEA to determine how it achieved its anorexic (decreasing body weight) effect.
The first assumption was that OEA, being similar to anandamide, must compete at the same receptors, blocking the eating response. However, OEA does not interact with the cannabinoid receptors, so they must act separately from the marijuana-derived chemical.5 Rather than hunting blindly for a chemical-receptor interaction, the researchers studied how OEA was created, what stimulus triggered its signal, and where it was made. They discovered that OEA is created from the cell membranes of the small intestine. They assumed that OEA must act locally, as it is rapidly broken down and would not survive to reach the brain directly.
The researchers tested the effect of OEA on the brain by injecting it directly into the brain ventricles (sinus-like cavities in the brain).5 There was no effect on eating, confirming that OEA does not act centrally (in the brain). Rather, it somehow triggers a separate signal that affects hunger and eating behavior. Lastly, the scientists used a chemical to destroy nerve endings in and around the small intestine where OEA is made. They discovered that OEA did not affect hunger or eating behavior in the rats whose nerve endings were destroyed. Thus, it seems OEA is sensed when it's formed in the gut and somehow triggers a nerve impulse that affects hunger and eating behavior.5

            OEA: Outlook Positive
The last step the researchers took was to treat rats with OEA for a number of days, and then remove the brain to see what regions of the brain were stimulated by the OEA treatment. Three distinct areas of the brain showed greater activity under the influence of OEA. These areas (paraventricular nucleus, supraoptic hypothalamic nucleus and the nucleus of the solitary tract) are all involved in appetite control by inducing satiety, or a feeling of fullness. Thus, the signal of OEA in the small intestine travels along the vagus nerve, to trigger a sense of satiety in the brain.5
This study was an exciting first step to understanding yet another route of appetite control. A second paper was recently published that better demonstrated how OEA works.10 Again, in studying rats, scientists learned that OEA is formed in the small intestine during a meal and OEA levels drop off sharply during periods of starvation. The specific receptor interaction was defined. OEA interacts with a class of receptors called peroxisome-proliferator-activated receptor - a, (PPAR-a). Using drugs that act on the PPAR-a receptor, the investigators confirmed that activation of that receptor caused the same effects as OEA.
The next step was even more interesting, as the scientists compared the effect of OEA in normal rats compared to those who did not have the PPAR-a receptor. The normal rats ate less and did not gain weight, as was expected, while the rats without the receptor were not affected by OEA. This confirmed that the actions of OEA are dependent upon interaction with the PPAR-a receptor.10
OEA is an exciting finding, in that it is a naturally occurring signal that shuts off hunger and can be effective in controlling the cravings and binges that are the bane of all bodybuilders. OEA is under development as a drug therapy for obesity, but it appears it may soon be available on the market as a dietary supplement.11 Remember, it occurs naturally in nearly all animal and plant cells. Once a suitable way to deliver OEA is developed and its effects are proven in humans, it promises to become a valuable tool in weight management for the obese and may stop the cravings that can reverse the fat loss achieved with pre-competition dieting.

References  

  1. Kernan WN, Viscoli CM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med, 2000 Dec 21;343:1826-32.
  2. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med, 2000 Dec 21;343:1833-38.
  3. Ernst ME, Hartz A. Phenylpropanolamine and hemorrhagic stroke. N Engl J Med, 2001 Apr 5;344:1094-5.
  4. Hutchins GM. Dietary supplements containing ephedra alkaloids. N Engl J Med, 2001 Apr 5;344:1095-7.
  5. Rodriguez De Fonseca F, Navarro M, et al. An anorexic lipid mediator regulated by feeding. Nature, 2001 November 8;414:209-212.
  6. Bachur NR, Masek K, et al. Fatty acid amides of ethanolamine in mammalian tissues. J Biol Chem, 1965;240:1019-24.
  7. Chapman KD. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem Phys Lipids, 2000;108:221-9.
  8. Di Marzo V, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons.Nature, 1994;372:686-91.
  9. Piomelli D, Beltramo M, et al. Endogenous cannabinoid signaling. Neurobiol Dis 1998;5:462-73.
  10. Fu J, Gaetani S, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-a. Nature, 2003 Sep 4;425:90-93.
  11. Personal communication with Scott Hagerman, Chemi Nutraceuticals, White Bear Lake, MN; September 9, 2003.

FAT ATTACK NOV 22

Posted by: Unknown توقيت نشر: 18:10 / comment : 0 , , , , , ,

Fat Attack
By Dan Gwartney, MD
Growth Hormone Secretagogues
A Tale of Two Pities

Growth hormone (GH) has long been considered the hormonal Fountain of Youth.1 In addition to aiding in tissue repair and bioenergetics, GH also has potent anabolic and lipolytic properties that are of particular interest to bodybuilders and athletes.2

A Widening Interest

GH use by healthy adults is limited due to legal restrictions and cost. Physicians are increasingly being prosecuted or professionally ostracized for treating age-related decline of GH. Prescribing GH to a healthy, young adult for the purposes of improving appearance or athletic performance is prohibited, subjecting physicians who violate this edict to a loss of his/her medical license and potential imprisonment.3 No athlete has yet been banned from a sport or lost endorsements because of GH, as no legally defensible test for the hormone currently exists, though the World Anti-Doping Agency (WADA) claims they are near to having an algorithm developed that can detect GH use.
Many companies have touted products that claim to increase GH by stimulating natural GH production and release. The limitation to circulating GH isn't production, as the body has stores of GH in the pituitary well in excess of what's released. Instead, an interactive network of releasing hormones, inhibitors and secretagogues regulate the endocrinological balance to prevent GH excess or deficit in healthy people.4 Athletes have learned that increasing GH levels through daily or near-daily injections promotes tissue healing, reduces body fat and may increase muscle mass. The elderly also have a strong interest in GH, as natural levels steadily decrease after age 30, a fact implicated in the age-related decline in physical and mental function.5 Thus, both groups have been following the developments, or lack thereof, of a class of drugs called GH secretagogues.
Several pharmaceutical companies, large and small, have developed GH secretagogues after it was discovered that small peptide fragments of the larger protein, growth hormone-releasing hormone (GHRH) can stimulate GH release from the pituitary.6 GHRH is a hormone produced in the hypothalamus, the gland in the brain that regulates many hormone levels. When the hypothalamus detects conditions that require the release of more GH, it releases GHRH, which travels directly to the pituitary to stimulate GH release. GHRH is too large a protein to be administered orally (meaning it can't be taken as a pill), but smaller fragments of GHRH can be effective orally. Most of the early secretagogue work revolved around fragments of GHRH.
Other stimulators of GH have been discovered, including a hormone produced by the stomach called ghrelin (pronounced gray-lin). Ghrelin interacts with a different class of pituitary receptors than GHRH, promoting GH release through a separate pathway.7 Ghrelin's name is a shortened form for GH-releasing protein. Pharmaceutical companies, including Pfizer, hastened to find novel drugs that might take advantage of the ghrelin pathways for stimulating GH release. Among these was a drug called capromorelin.8,9

An Unsuitable Candidate

Capromorelin is being referred to in the past tense, as Pfizer discontinued developing the drug in 2002 due to limited efficacy and reports of side effects that made it an unsuitable candidate for FDA approval.10 It's very difficult to obtain FDA approval for drugs designed to treat signs and symptoms of normal aging, as the FDA doesn't consider aging to be a disease and maintains very high standards for safety and efficacy.11 Other pharmaceutical powerhouses have also terminated their GH secretagogue programs, including Merck and Bristol-Myers Squibb.10,11
However, capromorelin recently made the news as one of the clinical investigators participating in a Pfizer study reported on results at the 2006 International Congress of Neuroendocrinology in Pittsburgh. Dr. George Merriam, professor of medicine at the University of Washington and a physician with the VA Puget Sound Health Care System, presented the findings of a multi-site study, which enrolled nearly 400 elderly adults between the ages of 65-84. Merriam stated that the subjects gained over 3 pounds of lean mass, improved physical function (activities like walking) and had higher GH and IGF-1 levels; side effects were minor and included fatigue, insomnia and hyperglycemia (high blood sugar).11,12
What wasn't disclosed in the media reports on this presentation was that Dr. Merriam's data was based on a study that terminated prior to 2002. The impression given most readers was that capromorelin was currently being actively developed and possibly moving toward FDA approval. A conversation with Stephen Lederer, senior director of media relations at Pfizer Global Research and Development confirmed that capromorelin was no longer being developed as of 2002, and that Dr. Merriam's data related to earlier clinical trials. Mr. Lederer noted that there was enthusiasm among some of the clinical investigators for further developing capromorelin, but that an exhaustive analysis by Pfizer deemed it an unsuitable candidate after $71 million had been spent on the project.
Needless to say, it was not a decision made lightly. Mr. Lederer provided the following quote: "We greatly respect Dr. Merriam and the other investigators we work with and value their opinions. In this case, we firmly believe the decision to discontinue was appropriate and was in the interests of patients. We saw some increase in body mass, but no significant improvement in physical function. We believed that the lack of functional improvement and the side effects we observed were unacceptable in a chronic-use medicine. Our considerable experience led us to believe that this risk/benefit ratio would not have been acceptable to regulatory agencies for the prevention of age-related declines in physical performance.13

A Growing Demographic

On a more positive note, the rights to Bristol-Myers Squibb's secretagogue program have been purchased by Elixir Pharmaceuticals, a smaller company that focuses on age-related diseases, so it's possible that future developments in this area may be announced.14 The growing demographic of aging baby boomers and the recognition of further benefits associated with preventing age-related GH decline such as improved mental performance, in addition to the physical benefits, ensure continued public interest in the field.15
Given the lack of an available secretagogue and the efficacy of GH and the natural stimulus to GH provided by exercise, why would any athlete be interested in GH secretagogues?16 Previous experiences with dietary supplements claiming to promote GH release have been variable, with many providing little apparent benefit. Amino acid-based GH releasers, though capable of inducing a greater GH release at rest, appear to actually inhibit exercise-induced GH release.17-19
Pharmaceutical GH secretagogues may offer several benefits that aren't currently available with GH. First, a number of orally active formulations have been developed. Though often short-acting, continuous-release capsules have been produced- even in the case of capromorelin. It's unclear whether a sustained, long-acting version of a secretagogue would provide any clinical benefits, as GH is released in several short bursts throughout the day rather than as a long, continuous flow. Nonetheless, injections could be avoided, reducing cost, storage problems, injection site trauma or infection, as well as any related pain or discomfort. Second, the other "regulators" of GH release would still be active in the body, reducing the risk of side effects related to GH excess. It's important to note that some side effects were still noted in Dr. Merriam's study group, but it's possible that a younger population may better tolerate the therapy. The observation of a higher risk of side effects in older subjects has been noted with testosterone therapy in men and estrogen therapy in women.20,21

The Return of Cadaveric GH

The last notable benefit relates to athletes who might abuse GH in sports doping. At this time, the International Olympic Committee (IOC) doesn't ban GH secretagogues as they're not commercially available, though expect WADA and related groups to respond more pro-actively after the revelations exposed during the BALCO scandals. While it's obvious that GH secretagogues could be used by athletes for the purpose of increasing GH, it's also possible that GH secretagogues could be used, even at this time, to foil the proposed GH-detecting algorithms suggested by WADA, allowing athletes to use the more potent and effective method of recombinant GH injections.
Here's how it might work: Currently, it's impossible to detect exogenous GH doping, as the recombinant product is identical to one form produced in the body.22,23 WADA has proposed to test athletes' blood (as opposed to urine, which is used in nearly every other test) for two different sets of markers. First, WADA would check to see if the form of GH present in commercially available products is present in greater amounts, compared to the other forms, than is naturally seen.24 This is similar to the 4:1 ratio of testosterone:epitestosterone that's used in some screens and was defeated by use of the "the cream." The cream contained both testosterone and epitestosterone, which lowered the testosterone:epitestosterone ratio back down to accepted levels, preventing a positive drug test.[Author's note- the ratio of testosterone to epitestosterone is the doping detection screen that prompted the allegations of testosterone use by 2006 Tour de France champion Floyd Landis].25
GH secretagogues could stimulate the release of natural GH, including all the isoforms tested for by the proposed WADA plan, restoring isoform ratios back to accepted levels. Of course, this would have to be titrated individually with each athlete, making it expensive, unless they were willing to chance it on a general program. This assumes that illicit manufacturers aren't providing GH products that include a natural combination of the various isoforms. One deadly risk that WADA may actually be propagating is the return of cadaveric GH.
Prior to the discovery of a method of producing GH via recombinant methods (meaning in a laboratory), GH was obtained by extracting it from the pituitary of dead people. This now-banned source, while once valuable to children being treated with the extract, exposed them and doping athletes to the risk of contracting a deadly disease called Creutzfeldt-Jakob disease, similar to mad cow disease.26,27 There's been at least one case of a French bodybuilder contracting Creutzfeldt-Jakob, possibly from cow-derived, cadaveric GH extract or tainted meat imported from Great Britain (England had an epidemic of mad cow disease at the time) or sporadically- as others of that era caught the disease.28,29 The French bodybuilder died at the age of 26.
The second leg of the GH-detection algorithm wouldn't be circumvented, as it looks for markers of GH action to determine if supraphysiologic GH levels existed in an individual athlete, such as insulin-like growth factor-1 (IGF-1) and type III procollagen (P-III-P).30 Considering that most athletes are healthy, active and young, it's likely that the threshold will have to be set fairly high. This would limit the total benefit that could be attained through GH and GH secretagogue use, though the window of opportunity would be greater for older athletes. Many athletes are extending their careers into their late 30s and early 40s, making this more relevant with each passing year.

Offering Great Promise to the Aging & Athletic

This article doesn't advocate the use of GH or GH secretagogues for doping purposes. Instead, it's a response to reports of archived data that has raised the hopes of those facing declining function due to aging, or those hoping for a safer and more convenient means of promoting optimal GH to improve appearance and performance. It also raises a prospective inquiry regarding attempts by doping athletes to violate the ethics and rules of organized sports.
GH therapy offers great promise to the aging and athletic. Secretagogues, such as capromorelin, may provide a bridging therapy to those who either choose to avoid GH injections, or seek less expensive alternatives. At this time, there's no pharmaceutical secretagogue commercially available, and it remains to be seen if any of these oral drugs will provide similar effects to GH over the long-term. Further, it will be interesting to see if protocols will be developed allowing those first experiencing signs and symptoms of GH decline in their 30s and 40s to access either GH or GH secretagogues. As has been suggested with research involving the hormones testosterone and estrogen, introducing the therapy early, rather than waiting until frailties manifest, may reduce risks. As the first of the baby boomers enter their 60s, perhaps this politically affluent generation will prompt changes in legal and professional restrictions.

References:
  • 1. Morley JE, Unterman TG. Hormonal fountains of youth. J Lab Clin Med, 2000;135:364-6.
  • 2. Llewellyn W. Human Growth Hormone (somatotropin). Anabolics 2005. Body of Science Press, Jupiter, FL;2005:288-90.
  • 3. Brundett R. Shortt gets jail; players not off hook. The State [South Carolina], 2006 July 18.
  • 4. Surya S, Symons K, et al. Complex rhymicity of growth hormone secretion in humans. Pituitary, 2006 Jul 15;[Epub ahead of print].
  • 5. Mooradian AD, Morley JE, et al. Endocrinology in aging. Dis Mon, 1988;34:393-461.
  • 6. No Author Listed. Pralmorelin: GHRP 2, GPA 748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN, KP-102D, KP-102LN. Drugs, R D 2004;5:236-9.
  • 7. Kojima M, Hosoda H, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature,1999;402:656-60.
  • 8. Carpino PA, Lefker BA, et al. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin. Bioorg Med Chem, 2003;11:581-90.
  • 9. Carpino PA, Lefker BA, et al. Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorg Med Chem Lett, 2002;12:3279-82.
  • 10. Cohen F. Quest for youth: How research on anti-aging pill lost momentum. Available at http://blog.crownstoneinsights.com/notes/archive/2006_07_01_archive.html, accessed July 28, 2006.
  • 11. Fox M. Drug, blood provide clues to healthy aging-meeting. Reuters News Service, 2006 Jun 21.
  • 12. Reedy J. Growth hormone stimulators improve physical function in older adults. Public Release - University of Washington, via EurekAlert! news service.
  • 13. Lederer S. Personal communication via phone and email, July 25, 2006.
  • 14. Elixir Pharmaceuticals. Elixir Pharmaceuticals licenses novel growth hormone secretagogue compound from Bristol-Myers Squibb for treatment of metabolic disorders. 2005 Apr 28. Press Release available at http://www.elixirpharm.com/company/pr/squibb_050205.pdf, accessed July 28, 2006.
  • 15. Arwert LI, Veltman DJ, et al. Memory performance and the growth hormone/insulin-like growth factor axis in the elderly: a positron emission tomography study. Neuroendocrinology, 2005;81:31-40.
  • 16. Weltman A, Weltman JY, et al. Growth hormone response to graded exercise intensities is attenuated and the gender difference abolished in older adults. J Appl Physiol, 2006;100:1623-9.
  • 17. Marcell TJ, Taaffe DR, et al. Oral arginine does not stimulate basal or augment exercise-induced GH secretion in either young or old adults. J Gerontology, 1999;54A:M395-399.
  • 18. Surninski RR, Robertson RJ, et al. Acute effect of amino acid ingestion and resistance exercise on plasma growth hormone concentration in young men. Int J Sport Nutr, 1997;7:48-60.
  • 19. Besset A, Bonardet A, et al. Increase in sleep related GH and Prl secretion after chronic arginine aspartate administration in man. Acta Endocrinol (Copenh), 1982;99:18-23.
  • 20. Bhasin S, Woodhouse L, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab, 2005;90:678-88.
  • 21. Naftolin F. Prevention during menopause is critical for good health: skin studies support protracted hormone therapy. Fertil Steril, 2005;84:293-4.
  • 22. McHugh CM, Park RT, et al. Challenges in detecting the abuse of growth hormone in sport. Clin Chem,2005;51:1587-93.
  • 23. Rigamonti AE, Cella SG, et al. Growth hormone abuse: methods of detection. Trends Endocrinol Metab,2005;16:160-6.
  • 24. Project Review. Transition from research lab to ISO-certified optimization and production of differential immunoassays for the detection of GH-doping in sports based on the isoform approach. World Anti-Doping Agency. Available at http://www.wada-ama.org/rtecontent/document/DrSoehnge.pdf, accessed July 28, 2006.
  • 25. Mann D. Innocent reasons for Landis dope test? WebMD Medical News 2006 July 27. Available at http://www.webmd.com/content/article/125/116062, accessed July 28, 2006.
  • 26. Brown P, Gajdusek DC, et al. Potential epidemic of Creutzfeldt-Jakob disease from human growth hormone therapy. N Engl J Med, 1985;313:728-731.
  • 27. Deyssig R, Frisch H. Self-administration of cadaveric growth hormone to power athletes. Lancet, 1993;341:768-769.
  • 28. Chazot G, Broussole E, et al. New variant of Creutzfeldt-Jakob in a 26-year-old French Man. Lancet, 1996;347:1181.
  • 29. Verdrager J. New variant Creutzfeldt-Jakob disease and bovine pituitary growth hormone. Lancet, 1998;351:112-3.
  • 30. Sonksen & Holt. The development of methodology for detecting growth hormone in sport:GH2004. World Anti-Doping Agency. Available at http://www.wada-ama.org/rtecontent/document/A1_2002_results.pdf, accessed July 28, 2006.

FAT ATTACK: FAT TRIMMING GH FRAGMNET APRIL 05

Posted by: Unknown توقيت نشر: 18:07 / comment : 0 , , , , ,


Fat Attack

By Dan Gwartney, MD

AOD9604

A Fat-Trimming Fragment of Growth Hormone


            Bodybuilding has experienced a number of quantum leaps. Once upon a time, it was mustachioed men clad in unitards performing calisthenics. The introduction of dumbbells and barbells produced mustachioed men in unitards lifting weights that looked more like car parts. Eventually, organized gyms evolved, mustaches were shaved and the unitards were trimmed down to tiny trunks.
            The changes evoked by training methods and facial hair styles were minimal compared to the dramatic changes seen during the last few decades. Eugene Sandow is a legend among early bodybuilders. A strongman who displayed his physique during the late 1800s and early years of the 1900s, Sandow is best known now as the figure personified in the Sandow trophy handed out each year to the winner of the Mr. Olympia. Despite his glorious reign as one of the founders of modern bodybuilding, Sandow's physique would have been easily overshadowed by most of the bodybuilders of the 1960s and 1970s. It was during this period that physiques were augmented through the use of anabolic steroids. Placing Sandow next to Arnold or Mike Mentzer in their prime would have made Sandow look like a child.
           
            Then hGH Arrived on the Scene
During the 1980s, a new drug trickled into the bodybuilding pharmacopoeia that greatly exaggerated the physiques appearing upon the stage: human growth hormone (hGH). It was not until the later 1980s that the use of hGH became relatively commonplace, but it's now considered a mandatory ingredient for professional bodybuilding success.1 Not only has hGH inflated muscle size, but it has also allowed bodybuilders to strip body fat down to cartoonish levels. The difference has been so great as to physically dwarf even Arnold of the 1970s. Other drugs, such as insulin, aromatase inhibitors and synthol, have added further changes, but hGH is definitely the most potent factor since testosterone esters.
            As noted, the benefits of hGH included both an anabolic effect (bigger muscles) and a lipolytic effect (less body fat), though scientists will dispute the fact that this offers any benefits to athletes.2 Obesity specialists have noted the lipolytic effect of hGH and found it's effective in treating overweight and obese people.3-6 However, using hGH is not without problems. If too high a dose is administered over a period of time, IGF-1 levels will exceed the therapeutic range and symptoms of hGH excess will develop. Edema, carpal tunnel syndrome, impaired glucose tolerance, enlarged organs, distorted facial features and even overt diabetes can arise if hGH is dosed inappropriately.7-9 Given the political backlash coming against hGH due to its role in sports doping, along with the expense of treatment and monitoring, the possibility of introducing hGH into standard treatment protocols for obesity seems remote. However, there is some promise looming on the horizon.
Growth hormone is a large protein.10 Proteins are long chains of amino acids that fold and wrinkle so certain parts are exposed on the surface, while others are crumpled up in the middle.11 Of the parts that are exposed, certain amino acid sequences are specifically structured to interact with receptors on the surface of cells. Though most people are taught to consider hormone and receptor interaction as a lock-and-key model, it appears that is oversimplified, at least for protein hormones. Rather than being a single key, large protein hormones like hGH seem to behave more like key rings, with two or more segments able to interact with different cells, bringing about a spectrum of biological effects, rather than a single effect.
For instance, hGH is known to interact with growth hormone receptor imbedded in the cell surface of fat cells, causing them to break down and release stored fats.12 It also interacts with the liver and other cells to signal the production of growth factors, such as the somatomedins and IGF-1. Different cells, different effects, same hormone.13
            It has long been suggested that hGH behaves like a prohormone in addition to being a direct hormone.14Small fragments are generated in the peripheral metabolism of hGH, some of which may retain biological activity.15Researchers have long looked at the activity of various structural segments and discovered separate functions of hGH segments.15,16 One researcher, Dr. F. Ng of Monash University, identified a specific segment located at one end of hGH that appears to be responsible for much of the lipolytic activity.15,17-28 This amino acid sequence interacts with the fat cell, stimulating the breakdown and release of stored fatty acids and glycerol (the components of stored fats or triglycerides).
Surprisingly, this effect does not appear to involve the hGH receptor. One study measured a significant increase inB3-adrenoreceptors in mice, a receptor for adrenaline and norepinephrine that stimulates fat loss; increases in B3-adrenoreceptors are seen with the use of hGH, as well.27,29 This fragment retains its ability to stimulate fat loss, even after being broken off the larger hGH molecule. It is a peptide chain of only 15 amino acids being developed by the Australian company Metabolic Pharmaceuticals Limited under the code name AOD9604.30

 AOD9604: Exciting Potential

AOD9604 offers exciting potential to the fat loss arsenal for three primary reasons. First, being a small peptide, the fragment can be administered orally (swallowed), as opposed to hGH which must be injected under the skin.31Second, it has been shown to be effective at a low dose, which makes it affordable and convenient. Third, it has no anabolic effect, meaning it does not increase IGF-1 or cause muscle or organ growth. Bodybuilders may see the last as a negative, but in fact, it may be a positive as it would likely allow AOD9604 to be approved for use in treating obesity before hGH, as the abuse potential and the risk of side effects would be much lower.
            Dr. Ng collaborated with Metabolic Pharmaceuticals Limited to further investigate the potential of AOD9604 in treating obesity. Together, they have advanced AOD9604 through phase 2b of drug development, demonstrating the effectiveness of the drug in reducing weight of obese subjects.
            Prior studies involving AOD9604 included a number of bench top experiments and animal studies, demonstrating the ability of the drug to stimulate the release of stored fat from fat cells observed in a test tube, as well as reducing weight gain in growing mice.15,17-28,31
            In a 12-week placebo controlled study, groups of obese people were treated with five different levels of AOD9604 along with general diet and exercise advice.32 Three hundred subjects were involved in the study. During the study, no adverse side effects were noted and the test subjects lost more weight than the control group. The most significant weight loss occurred with the group taking the lowest dose of the drug, which is surprising in some aspects. However, this effect had been noted in the earlier studies. The company's press release stated that one milligram of AOD9604 is actually the biologic equivalent of a very high dose of hGH.30
            Additional benefits of AOD9604 treatment were observed during the study. Changes in cholesterol were charted that would decrease cardiovascular risk, including a decrease in LDL (bad) cholesterol and an increase in HDL (good) cholesterol. Glucose tolerance, a measure of how well the body handles sugar, was also improved. Impaired glucose tolerance is often seen in obese people and is often a warning sign of future diabetes. Even though the actions of hGH are known to stimulate the production of IGF-1, a potent growth mediator, no changes in IGF-1 levels were noted in any of the groups. This further demonstrates that separating the lipolytic effect from the anabolic effect of hGH was achieved.32
            The successful trial of AOD9604 opens an avenue of opportunity, but first the drug must complete the FDA approval process in order to be cleared for worldwide marketing. This will involve a larger study, which is projected to begin later this year. Though it has taken nearly 30 years to reach this point, it appears this drug may become available as a treatment option for those needing help with weight management. If the B3-adrenoreceptor effect is seen in humans, then adding a sympathomimetic combination like ephedrine/caffeine could further increase the effect of treatment.

            What's in it for the Bodybuilder?
To the competitive bodybuilder, separating the anabolic effect out of hGH may seem sacrilegious. Considering the impact hGH has had on the sport of bodybuilding, it's unlikely any serious competitors would opt for AOD9604 as opposed to Nutropin (synthetic hGH). For those who might be satisfied with a less exaggerated physique, but desire a leaner appearance (not to mention better cholesterol levels), AOD9604 may one day be a legitimate option. Being able to avoid daily injections by taking AOD9604 as a tablet will increase its appeal compared to hGH for many. It is unlikely that hGH will be approved for cosmetic or performance purposes any time in the near future. Perhaps by piecing out the valuable parts of hGH, society will be able to access the therapeutic potential of this potent hormone.

References 

  1. Llewellyn W. Human Growth Hormone (somatotropin). Anabolics 2004. Molecular Nutrition Press, Jupiter, FL;2004:236-8.
  2. Rennie MJ. Claims for the anabolic effects of growth hormone: a case of the emperor's new clothes? Br J Sports Med, 2003 Apr;37(2):100-5.
  3. Moller N, Gjedsted J, et al. Effects of growth hormone on lipid metabolism in humans. Growth Horm IGF Res,2003 Aug;13 Suppl A:S18-21.
  4. Takahashi S, Satozawa N. The 20-kD human growth hormone reduces body fat by increasing lipolysis and decreasing lipoprotein lipase activity. Horm Res, 2002;58(4):157-64.
  5. Lucidi P, Parlanti N, et al. Short-term treatment with low doses of recombinant human GH stimulates lipolysis in visceral obese men. J Clin Endocrinol Metab, 2002 Jul;87(7):3105-9.
  6. Albert SG, Mooradian AD. Low-dose recombinant human growth hormone as adjuvant therapy to lifestyle modifications in the management of obesity. J Clin Endocrinol Metab, 2004 Feb;89(2):695-701.
  7. Dickerman RD, Douglas JA. Bilateral median neuropathy and growth hormone use: a case report. Arch Phys Med Rehabil, 2000 Dec;81(12):1594-5.
  8. Blackman MR, Sorkin JD, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA, 2002 Nov 13;288(18):2282-92.
  9. Halac I, Zimmerman D. Managing growth hormone treatment in pediatric patients. Pediatr Ann, 2004 Mar;33(3):183-8.
  10. Lewis UJ, Sinha YN, et al. Structure and properties of members of the hGH family: a review. Endocr J, 2000 Mar;47 Suppl:S1-8.
  11. Kopchick JJ. History and future of growth hormone research. Horm Res, 2003;60 Suppl 3:103-12.
  12. Asada N, Takahashi Y, et al. GH induced lipolysis stimulation in 3T3-L1 adipocytes stably expressing hGHR: analysis on signaling pathway and activity of 20K hGH. Mol Cell Endocrinol, 2000 Apr 25;162(1-2):121-9.
  13. Ohlsson C, Sjogren K, et al. The relative importance of endocrine versus autocrine/paracrine insulin-like growth factor-1 in the regulation of body growth. Pediatr Nephrol, 2000 Jul;14(7):541-3.
  14. Palidini AC, Pena C, et al. The intriguing nature of multiple actions of growth hormone. Trends in Biochemical Sciences 1979;4:256-60.
  15. Ng FM, Sun J, et al. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone.Horm Res, 2000;53:274-8.
  16. Ng FM. A comparison of cellular actions between gliclazide and a hypoglycaemic peptide fragment of human growth hormone (hGH 6-13). Diabetes Res Clin Pract, 1988 May 19;5(1):17-24.
  17. Wade JD, Pullin CO, et al. The synthesis and hyperglycaemic activity of the amino acid sequence 172-191 of human growth hormone. Biochem Biophys Res Commun, 1977 Sep 23;78(2):827-32.
  18. Ng FM, Bornstein J. Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. Am J Physiol, 1978 May;234(5):E521-6.
  19. Wade JD, Ng FM, et al. Diabetogenic action of human growth hormone. Synthesis and activity of C-terminal fragments. Int J Pept Protein Res, 1979 Feb;13(2):195-200.
  20. Wade JD, Ng FM, et al. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177-191. Acta Endocrinol, 1982 Sep;101(1):10-4.
  21. Bornstein J, Ng FM, et al. Metabolic actions of pituitary growth hormone. I. Inhibition of acetyl CoA carboxylase by human growth hormone and a carboxyl terminal part sequence acting through a second messenger. Acta Endocrinol, 1983 Aug;103(4):479-86.
  22. Wu Z, Ng FM. Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone.Biochem Mol Biol Int, 1993 May;30(1):187-96.
  23. Wijaya E, Ng FM. Effect of an antilipogenic fragment of human growth hormone on glucose transport in rat adipocytes. Biochem Mol Biol Int, 1993 Nov;31(3):543-52.
  24. Natera SH, Jiang WJ, et al. Reduction of cumulative body weight gain and adipose tissue mass in obese mice: response to chronic treatment with synthetic hGH 177-191 peptide. Biochem Mol Biol Int, 1994 Aug;33(5):1011-21.
  25. Ng FM, Jiang WJ, et al. Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. J Mol Endocrinol, 2000;25:287-98.
  26. Ogru E, Wilson JC, et al. The conformational and biological analysis of a cyclic anti-obesity peptide from the C-terminal domain of human growth hormone. J Peptide Res, 2000;56:388-97.
  27. Heffernan M, Summers RJ, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and B3-AR knock-out mice. Endocrinol,2001;142(12):5182-9.
  28. Heffernan MA, Thorburn AW, et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes, 2001;25:1442-9.
  29. Yang S, Mulder H, et al. Effects of growth hormone on the function of beta-adrenergic subtypes in rat adipocytes. Obes Res, 2004 Feb;12(2):330-9.
  30. Belyea C, Kenley D. Press Release: Successful trial results for world-first obesity drug. Metabolic Pharmaceutical Limited, Melbourne, Australia. 2004 Dec 13.
  31. Heffernan MA, Jiang WJ, et al. Effects of oral administration of a synthetic fragment of human growth hormone on lipid metabolism. Am J Physiol Endocrinol Metab, 2000;279:E501-7.
  32. Wittert G, et al. Company news: AOD9604 phase 2b clinical trial successful. Metabolic Pharmaceutical Limited, Melbourne, Australia; 2004 Dec 13.

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