Science, Weeklies

Lose Weight With Your Brain

Scientists target a new part of the body to combat weight loss.

Weight loss is an obsession upon which the diet industry feeds, supplying numerous weight loss programs, pills and patches. There are the well-known, celebrity-endorsed programs and products, such as Weight Watchers and Zantrex-3, which involve diet and lifestyle changes. Then there are the lesser-known diet tactics, including earrings designed to decrease hunger by stimulating acupuncture points.

“I would say weight loss is a big deal to most people, especially girls,” said Kristina Woolf, a freshman in College of Arts and Sciences. “And they usually don’t want to lose weight in order to be more healthy. They sacrifice their health to look a certain way.”

The latest focus of weight loss drug manufacturers is the endocannabinoid system. Located throughout the body, endocannabinoid receptors and proteins play a key role in the regulation of numerous physiological—including hunger.

In June of 2006, Rimonabant, a weight loss drug sold by pharmaceutical company, Sanofi-Aventis, became available in Europe. Rimonabant targeted the CB1 endocannabinoid receptors in the brain to suppress hunger.

In the summer of 2007, rimonabant had been rejected by the U.S. Food and Drug Administration due to numerous reports of adverse side effects including nausea, depression and suicidal tendencies. In December of 2008, after addressing health concerns per request of the European Medicines Agency, Sanofi-Aventis removed rimonabant from the markets in Europe.

OUT OF THE BRAIN, INTO THE GUT

The issue with rimonabant was that it interfered with the body’s ability to produce dopamine, a neurotransmitter responsible for regulating the reward and pleasure centers of the brain. Without the ability to attain a natural high, a person taking rimonabant was more susceptible to depression.

Dr. Keith Sharkey, a neuroscientist studying endocannabinoids in the stomach at the University of Calgary, along with medical chemist Alexandros Makriyannis and a team, synthesized a compound to mimic rimonabant with a few important changes.

The compound, AM6545, targets the CB1 receptors in the stomach but remains outside of the brain. They theorized that the compound would promote weight loss just as rimonabant had done without compromising the dopamine levels in the brain.

In animal trials, AM6545 has been a success. A study in the British Journal of Pharmacology reports that mice and rats on AM6545 had lost weight without any side effects of nausea or depression.

The question that remains is whether or not the compound will have the same effect in humans. Research has found that the placement and distribution of endocannabinoid receptors is different among species. Still, the compound is a step in the right direction.

“I’m optimistic. I would say that humans would lose weight, that they would have improved metabolic profile. I would hope that they would have less or no side effects,” Sharkey said in an email interview.

The compound might also be able to maintain effectiveness without any lifestyle changes.

“In our preclinical studies we do see effects whilst animals are maintained on a high fat diet,” Sharkey said.

Despite the promise AM6545 demonstrates, Sharkey said that the compound should not be used as quick fix or permanent solution for obese or overweight individuals

“I would imagine that once a stable reduced weight was accomplished it would make sense to use lifestyle changes to maintain it, and not have to use a drug,” he said.

QUICK FIX FOR WEIGHT LOSS?

The development of a drug that could be used to achieve an ideal weight without any real effort, as demonstrated by AM6545, does not seem to be improbable. The utility of such a drug as the only method of treatment for obesity is not recommended.

“Since the etiology of obesity is complex, it only makes sense that the treatment requires a multipronged approach. Standard treatments include both medical and nutritional management,” said Kelli Swensen, Social Media Manager for Sargent Choice Nutrition Center in an email interview. “Weight loss requires a total lifestyle change that can only be completely achieved by lifestyle modification, including changes to behavior.”

While there is no quick fix for obesity or an easy way to lose weight, many people are attracted to the idea of such options.

“I feel like people would abuse a drug that could make people lose weight without really doing anything because it would be a quick and easy solution,” said Martine Trembelay, a sophomore in CAS. “I’m not saying that a drug like that should not be made but it definitely should not be marketed.”

BACK INTO THE BRAIN

Researchers’ interest with the endocannabinoid system does not end with hunger and obesity. Many believe that further research could result in new drugs for numerous diseases, addictions and ailments such as alcoholism, epilepsy, depression, pain, anxiety and Parkinson’s disease.

The system’s involvement in managing dopamine levels makes it a prime target in the treatment of addiction to dopamine-boosting drugs.

Zheng-Xiong Xi, a pharmacologist at the National Institute on Drug Abuse in Baltimore, figured that interfering with the CB1 receptors to decrease dopamine levels, similar to the way rimonabant worked, would deny cocaine users the high associated with the drug.

To test his theory, Xi studied the effects of THC, the active compound in marijuana, which is believed to increase dopamine levels by stimulating CB1 receptors, in the brain. Instead of finding the dopamine levels rising with a dose of THC, Xi found that they dropped.

The same dopamine decrease occurred in mice without CB1 receptors. The only way this could be possible would be if THC was acting on CB2, the other endocannabinoid receptor, instead of CB1. This possibility was strange considering that CB2 receptors were thought to be located outside of the brain.

To discover whether or not CB2 receptors were in the brain, Xi used JWH-133, a dopamine-decreasing compound developed to attach to CB2 receptors. He found that the dopamine levels decreased in the brain which confirmed that CB2 receptors had to be located there. He also found that the compound reduced the number of times cocaine-addicted mice pushed a lever for a shot of cocaine. In addition, the mice exhibited no adverse side effects.

STAY IN THE BRAIN

Xi’s discovery suggested there could be an alternative to Sharkey’s method of avoiding the brain all together. Rather than targeting the same CB1 receptor in a different area of the body, an effective drug for weight loss could target the CB2 receptor instead.

The very nature of the CB2 receptors makes them a likely focus in the research for new drugs.

“The problem with the CB1 receptor is the fact that it is one of the most widely distributed, highly expressed receptor,” Sharkey said. “The CB2 receptors have a much more restricted distribution so you can target them more with a less potential for side effects.”

The endocannabinoid system presents an opportunity and a challenge for researchers and drug designers. There is no doubt that continued research on the system will yield new types of treatments and therapies for numerous conditions. Nevertheless, there is always a risk of unwanted side effects and the far reaching influence of the endocannabinoid system increases that likelihood.

“I think it is a worthy investment of our research,” said Adnan Hussain, a freshman in CAS. “The fact that the system is found throughout the body probably means we will learn more about the body in the process.”

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