Diet-induced obesity has become a worldwide epidemic, with nearly 40% of the adult population affected by overweight or obesity. This disease increases mortality, as well as the likelihood of suffering more than one disorder simultaneously. Furthermore, it is closely related to the risk of developing cancer. At the present time, we still do not know much about the majority of the mechanisms involved in the harmful effects of obesity, a fact that makes it difficult to access viable therapeutic strategies or develop new treatments to fight it.
Now, researchers from the IDIBAPS Translational Control of Liver Disease and Cancer group, led by Mercedes Fernández-Lobato, have identified the protein CPEB4 as a potential therapeutic target against obesity.
According to the results, published in the journal Molecular Metabolism, a diet rich in fats increases the expression of CPEB4 in the adipose tissue of humans and mice. This activates a set of genes involved in expansion of the adipose cells, inflammation, and an increase in body fat. Furthermore, CPEB4 contributes to the alteration of the intestinal microbiota associated with obesity, as it increases the proportion of bacterial species considered as pathological.
However, the deletion of the CPEB4 gene in mice inhibits the differentiation of adipocytes. In addition, it also reduces the accumulation of lipids in the abdominal cavity, the inflammation of adipose tissue, and the weight increase, even if the animals receive a diet rich in fats. Finally, the absence of the protein normalizes the composition of the microbiome and favors the presence of bacteria that protect the intestinal barrier.
“Our work reveals the existence of a circuit that regulates the process of translation of RNA to proteins, directed by CPEB4, that was unknown to date”, explains Fernández-Lobato. “This represents an important new discovery since, to date, research has been focused mainly on the prior step, in other words, the synthesis of RNA from DNA. Therefore, our results promote a change of model towards translational control, which can open up new research pathways for developing better treatments against obesity”.
The study, signed by Núria Pell as the first author, represents a step forward that will enable the group to study in depth, and understand, the mechanisms that increase the risk of suffering liver cancer among obese people.
Nuria Pell, Ester Garcia-Pras, Javier Gallego, Salvador Naranjo-Suarez, Alexandra Balvey, Clara Suñer, Marcos Fernandez-Alfara, Veronica Chanes, Julia Carbo, Marta Ramirez-Pedraza, Oscar Reina, Louise Thingholm, Corinna Bang, Malte Rühlemann, Andre Franke, Robert Schierwagen, Karl P Rheinwalt, Jonel Trebicka, Raul Mendez, Mercedes Fernandez. Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Molecular Metabolism, 2021 Nov 10;54:101388. doi: 10.1016/j.molmet.2021.101388