Reducing obesity in mice

Blocking a protein called CB1R in mice makes their livers more responsive to a hormone called leptin, which regulates appetite and metabolism.
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Image showing the fatty deposits in the liver of a mouse which is less responsive to leptin (yellow) due to the enhanced activity of CB1R (green). Image credit: German Wegbrait (CC BY 4.0).

When the human body has stored enough energy from food, it releases a hormone called leptin that travels to the brain and stops feelings of hunger. This hormone moves through the bloodstream and can affect other organs, such as the liver, which also help control our body’s energy levels. Most people with obesity have very high levels of leptin in their blood, but are resistant to its effects and will therefore continue to feel hungry despite having stored enough energy.

One of the proteins that controls the levels of leptin is a receptor called sOb-R, which is released by the liver and binds to leptin as it travels in the blood. Individuals with high levels of this receptor often have less free leptin in their bloodstream and a lower body weight. Another protein that helps the body to regulate its energy levels is the cannabinoid-1 receptor, or CB1R for short. In people with obesity, this receptor is overactive and has been shown to contribute to leptin resistance, which is when the brain becomes less receptive to leptin. Previous work in mice showed that blocking CB1R reduced the levels of leptin and allowed mice to react to this hormone normally again, but it remained unclear whether CB1R affects how other organs, such as the liver, respond to leptin.

To answer this question, Drori et al. blocked the CB1R receptor in the liver of mice eating a high-fat diet, either by using a drug or by deleting the gene that codes for this protein. This caused mice to have higher levels of sOb-R circulating in their bloodstream. Further experiments showed that this change in sOb-R was caused by the levels of a protein called CHOP increasing in the liver when CB1R was blocked. Drori et al. found that inhibiting CB1R caused these obese mice to lose weight and have healthier, less fatty livers as a result of their livers no longer being resistant to the effects of leptin.

Scientists, doctors and pharmaceutical companies are trying to develop new strategies to combat obesity. The results from these experiments suggest that blocking CB1R in the liver could allow this organ to react to leptin appropriately again. Drugs blocking CB1R, including the one used in this study, will be tested in clinical trials and could provide a new approach for treating obesity.