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Anti-obesity compound

New drug sensitises leptin leading to weight loss

JD5037 compund successfully suppresses the appetite of obese mice leading to weight loss
Outcomes show improvements in metabolic health with no anxiety or behavioural side effects
George Kunos

A drug compound that increases sensitivity to the hormone leptin, thereby suppressing appetite, could have implications for the development of new treatments for obesity in humans. The study was published in the journal Cell Metabolism.

"By sensitising the body to naturally occurring leptin, the new drug could not only promote weight loss, but also help maintain it," said senior study author George Kunos of the National Institute on Alcohol Abuse and Alcoholism. "This finding bodes well for the development of a new class of compounds for the treatment of obesity and its metabolic consequences."

Although leptin is an appetite suppressant, leptin supplements alone have not been effective at reducing body weight in humans. It is believed that the human body becomes desensitised to the hormone over time, lessening its response.

Researchers do not know why desensitisation occurs; however, it has been hypothesised that cannabinoid receptors, which mediate the feelings of hunger produced by cannabis and naturally occurring cannabinoids in the body, are involved in the process.

In this study, investigators tested a new compound, JD5037, which targets cannabinoid receptor type 1 (CB1R) without penetrating the brain. They report that not only did JD5037 suppress the appetite of obese mice leading to weight loss, it also improved metabolic health.

Appetite and weight reduction caused by JD5037 are mediated by resensitising mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes, and increasing leptin clearance via the kidney.

Importantly, the mice did not show signs of anxiety or other behavioural side effects.

Previously, researchers have concentrated on blocking these receptors believing it could be more effective at long-term weight loss and developed anti-obesity drugs that target CB1R. However, only one CB1R-binding drug (rimonabant) was sold in Europe beginning in 2006 and it was taken off the market a few years later due to serious psychiatric side effects, including anxiety, depression and thoughts of suicide.

In order to reduce these side-effects, Kunos and his team developed a CB1R-targeting drug that did not enter the brain as easily as rimonabant. However, the drug was not as effective at reducing weight and improving metabolic health, possibly because of its specific mode of action.

“This study shows that inverse agonism at peripheral CB1R not only improves cardiometabolic risk in obesity but has anti-obesity effects by reversing leptin resistance,” said Kunos. “Obesity is a growing public health problem, and there is a strong need for new types of medications to treat obesity and its serous metabolic complications, including diabetes and fatty liver disease.”

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