The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.
Keywords: CHOP; ER stress; cb1 receptor; cell biology; endocannabinoids; leptin resistance; mouse; obesity.
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.
© 2020, Drori et al.