Role of Adipocyte Vacuolar H+ ATPase in Energy Balance and Glucose Homeostasis
Weight loss is one of the most effective treatments for Type 2 diabetes such that even a modest weight loss can lead to massive improvements in metabolic function. However, weight loss is not easy to achieve, harder to maintain and yet the mechanisms of weight regain are poorly described. We investigated the “metabolic memory of obesity” that may play a role in weight regain. We identified genes that are persistently in an obese state in key metabolic tissues of formerly obese mice. We discovered that the metabolic memory resides predominantly in the fat tissue. We then used a novel and innovative worm-based assay to investigate the effect these genes on food intake. We found that worms lacking the gene Atp6v0a1, a subunit of the lysosomal vacuolar H+ ATPase(V-ATPase), had decreased food intake. We generate an fat cell specific Atp6v0a1 mutant mouse and found that they decreased weight gain and food intake, and improved glucose tolerance in obese mice. In addition, drug-based inhibition of V-ATPase also reduced food intake and retarded weight regain. The goal of this project is to determine the mechanism by which V-ATPase in fat cells in regulating energy balance and glucose homeostasis. We believe that a better understanding of these mechanisms can lead to targeted approaches than can perturbed weight regain and improve glucose control after weight loss.