FAT ATTACK JAN 18

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.