BUD23 drives system-wide adaptations to energy metabolism

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Maintenance of our metabolic health is emerging as a major challenge of our time. The consequences of obesity include cardiovascular and metabolic disease (eg type 2 diabetes), as well as increased cancer, musculoskeletal (eg osteoarthritis), and infectious disease risk, notably corona virus mortality. Therapeutic approaches to body weight regulation have focused on appetite regulating pathways in the brain or nutrient absorption in the gut; with neither approach yielding adequate success. Therefore, new, effective and safe strategies are needed. Our proposal investigates the function of relatively unknown enzyme, BUD23, in regulating body weight, body composition and energy metabolism. Genetic studies in humans have associated BUD23 and its partner TRMT112 to obesity and elevated circulating triglycerides, and our studies in mice suggest that the action of this factor may be particularly influential in adipose tissue and the liver, key sites regulating our response to food intake, fasting and obesity. BUD23 is an established and conserved regulator of ribosomal maturation, the component of the cell responsible for making proteins. Our work to date suggests that the impact of BUD23 on ribosome function is selective, and has a particularly strong influence over production and functioning of mitochondria (a critical site of energy metabolism within our cells). Indeed, we find that deletion of BUD23 specifically from adipose tissue in mice re-programmes the balance of energy storage and expenditure (use), and results in a significantly lower proportion of body fat. In this proposal, we will fully define the role of BUD23 in directing metabolism in key tissues to gain therapeutic insight and target processes, and delineate the fundamental mechanisms (from translation efficiency to mitochondrial function). This work is in line with MRC priorities in nutrition and obesity.Specifically, we will investigate the phenotype of BUD23 in adipose and liver, and examine how BUD23 in these tissues regulates responses to high fat diet. We will explore links between BUD23 action and the cellular metabolic circadian clock, as our evidence to date reveals a striking loss of the typical change in energy substrate utilisation through circadian time when BUD23 is deleted in adipose. We will also investigate links between BUD23 and mitochondria dynamics and activity through proteomic and functional assessment in genetically targeted tissues. Finally, we will use ribosome profiling to identify the mechanism responsible for selective impacts on mRNA translation efficiency, which we think are encoded in mRNA sequences. We will integrate mRNA expression, mRNA translation, and steady-state protein abundance, using computational approaches to build an integrated model of how RNA biology affects energy metabolism, and how these processes may be therapeutically targeted.