Researchers Identify Endocannabinoid Signaling as a Pharmaceutical Target for Obesity

New research by scientists at the University of California, Riverside shows that chronic consumption of a western diet leads to overeating and obesity due to elevations in peripheral endocannabinoid signalling.

The endocannabinoid system is located throughout the mammalian body, including the brain and all peripheral organs, and participates in the control of many physiological functions in the body, including food intake, energy balance, and reward. It is comprised of lipid signalling molecules called endocannabinoids, which can be thought of as the body’s own “natural cannabis”, that bind to cannabinoid receptors located on cells throughout the body.

“Our research shows that targeting cannabinoid receptors in the periphery with pharmacological inhibitors that do not reach the brain, holds promise as a safe therapeutic approach for the treatment of overeating and diet-induced obesity,” said Nicholas V. DiPatrizio, an assistant professor of biomedical sciences in the School of Medicine. “This therapeutic approach to targeting the periphery has substantial advantages over traditional drugs that interact with the brain and cause psychiatric side-effects.”

To examine the role for endocannabinoids generated in peripheral organs in controlling the overeating of western diet, DiPatrizio and coauthor Donovan A. Argueta, used a mouse model of western diet-induced obesity. They found that when compared to mice fed a standard low-fat/low-sugar diet, mice fed a western diet for 60 days rapidly gained body weight and became obese, and consumed significantly more calories and larger meals at a much higher rate of intake.

“These hyperphagic responses to western diet were met with greatly elevated levels of endocannabinoids in the small intestine and circulation,” DiPatrizio said. “Importantly, we found that blocking the actions of the endocannabinoids with pharmacological inhibitors, we completely normalized food intake and meal patterns in western diet-induced obese mice to levels found in control mice.”

DiPatrizio and Argueta caution that further research is necessary to identify whether similar mechanisms drive obesity in humans. “Importantly, however, other research groups have reported elevations in circulating levels of endocannabinoids in obese human subjects, which suggests that this system may also be overactive in human obesity,” DiPatrizio said. He explained that rimonabant, a drug which blocked endocannabinoid signalling at cannabinoid receptors, was on the market in Europe for the treatment of human obesity.

“It worked quite well at reducing body weight and improving metabolic profiles; however, this drug was not restricted to the periphery and thus, led to severe psychiatric side effects and was not given FDA approval in the United States,” DiPatrizio said. “Peripherally restricted inhibitors of cannabinoid receptors, such as AM6545 used in our experiments, however, would be devoid of these side effects given that they do not reach the brain.”

DiPatrizio and Argueta were surprised to find that inhibiting peripheral endocannabinoid signalling with inhibitors like AM6545, completely normalized intake to that found in lean mice maintained on a standard chow. “This suggests that these elevations in peripheral endocannabinoid signalling are critical in driving hyperphagia associated with a western diet,” said Argueta, the first author of the research paper.

Next, the researchers plan to identify critical upstream and downstream mechanisms of endocannabinoid signalling in western diet-induced obesity, as well as the possible specific dietary constituents in western diet (e.g., sucrose) that drive overeating as a result of elevated peripheral endocannabinoid levels.

Reference:
Argueta, D. A., & DiPatrizio, N. V. (2017). Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiology & Behavior, 171, 32–39. doi:10.1016/j.physbeh.2016.12.044

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