It was strongly suspected but never evidenced: the role of Suv420h in the regulation of metabolism could be the first step towards new, more effective treatments for obesity and metabolic syndrome. Thanks to tests on mice, the project team has found that organisms lacking Suv420h proteins benefit from improved metabolic functions. They are also resistant to diet-induced obesity. An exciting finding “When fed with a high-fat containing diet, mice without the Suv420h1 and Suv420h2 enzymes gained less weight compared to control mice in which their expression was normal,” says Dr Simona Pedrotti, Postdoc fellow at HSR Research and coordinator of EASY (Epigenetic approach for the treatment of obesity). “This clearly demonstrates that the epigenetic regulators Suv420h control metabolism and body weight in response to environmental stimuli.” Prior to the project, environmental factors were known to modulate the aberrant expression of several key genes through epigenetic mechanisms. In the case of obesity and other metabolic disorders, dietary factors seemingly alter the epigenome in several human tissues of importance for metabolism. This, in turn, can affect gene expression and pathogenesis. “The most exciting aspect of our finding is that Suv420h proteins regulate metabolism by directly inhibiting the expression of PPAR-γ – a master transcriptional regulator of lipid storage and glucose homeostasis. This was of great interest to us. While PPAR-γ ligands of the thiazolidinedione class are already used as insulin sensitisers in the treatment of diabetes, their use has been limited by adverse effects. These include heart failure, fluid retention and bone fragility. Our results, on the other hand, indicate that targeting Suv420h could help in dissociating the benefits of PPAR-γ activation from its side effects,” Dr Pedrotti explains. When Suv420h is depleted Besides the improvement in metabolic function, the team found that Suv420h depletion is associated with several systemic effects. Mice lacking Suv420h proteins indeed present an increased number of ‘beige’ adipocytes within their white adipose tissue. “The beige adipocyte is a type of adipose cell able to produce heat and increase energy expenditure. These cells possess characteristics between those of the white fat cell – an accumulator of energy – and the brown cell which produces heat. Beige adipocyte has recently generated much interest because of its ability to dissipate energy,” says Dr Pedrotti. The depletion of Suv420h proteins in mice also results in increased expression of genes encoding for secreted proteins known to act on other tissues and stimulate energy expenditure. All these findings tend towards an improvement in metabolic function upon Suv420h depletion. The project consortium went a step further by describing the first epi-drug able to activate brown adipose cell metabolic activity, which is disrupted in obesity. They found that Suv420h inhibition is not toxic to brown adipocytes. It is also sufficient to activate both PPAR-γ expression and mitochondria respiration. In vivo inhibition has proved unfeasible so far, but the team is currently looking into ways to overcome this issue. The project, which was undertaken with the support of the Marie Skłodowska-Curie programme, is scheduled for completion at the end of 2019. In the meantime, the team intends to investigate whether depletion of Suv420h also has beneficial effects on other metabolic conditions, and particularly diabetes.
EASY, Suv420h, obesity, metabolism, metabolic syndrome, PPAR-γ, adipocyte