Obesity and its associated complications are increasing in prevalence worldwide. This highlights the need to find therapeutics to reduce the development and progression of obesity, and to better treat downstream complications such as lipotoxicity. Recently, we engaged a systems genetics approach utilising genetically diverse mouse strains, to identify novel proteins and pathways important in the regulation of lipid metabolism. This approach identified proteasome 26S subunit non-ATPase 9 (PSMD9) as a putative novel lipid regulatory protein. We demonstrated a causal role for PSMD9 in the regulation of hepatic lipid abundance, using both overexpression and silencing (anti-sense oligonucleotides - ASOs) approaches in vivo. Subsequently, we demonstrated that administration of PSMD9-ASO to mice fed a high cholesterol, high fructose AMLN diet over a 6-month period, led to improved metabolic readouts of obesity, including a significant reduction in weight gain, lower blood glucose levels, and improved indices of fatty liver. Such findings are consistent with human genetic data demonstrating that mutations in PSMD9 are associated with readouts of obesity in the UK Biobank, and with the incidence of diabetes and obesity in some European populations.
In the present study, we investigated whether PSMD9-ASOs could regress established obesity and its complications – a scenario similar to that which would occur in the clinic. We demonstrated that silencing PSMD9 in high fat diet fed obese mice significantly reduced body weight compared with control ASO treated mice. This was driven almost exclusively by reductions in fat mass, and was not due to changes in food intake, energy expenditure or off-target effects of the ASO. This reduced fat mass led to significant improvements in glucose and insulin tolerance after just 6 weekly doses. Thus, our studies highlight PSMD9-ASOs as a potential injectable treatment for obesity and its complications.