Endocannabinoids (ECs) are signalling molecules that regulate appetite, mood and pain, and they are studied mostly for their effects on the nervous system. Now, on p. , Wolfram Goessling and colleagues uncover a role for EC signalling during liver development and function in zebrafish. Using a chemical screen to identify novel regulators of liver development, the researchers reveal that EC agonists cause an increase in liver size. In line with this, they show that the EC receptors Cnr1 and Cnr2 are expressed in the liver and hepatic region of developing embryos. The TALEN-mediated knockout of these receptors disrupts the differentiation and proliferation, but not the specification, of hepatocytes, giving rise to livers that exhibit architectural and metabolic defects. These defects have a negative long-term impact, causing susceptibility to metabolic insult and disruptions to global lipid metabolism in adult fish. Finally, the authors reveal that the effects of EC signalling are mediated by methionine and by sterol regulatory element-binding transcription factors (Srebfs); methionine supplementation or the overexpression of Srebfs can rescue the liver defects of Cnr mutants. Together, these findings define exciting and novel links between EC signalling, methionine metabolism and liver development.
