Crucial roles of UCH-L1 on insulin-producing cells and carbohydrate metabolism in Drosophila melanogaster model.

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a highly expressed protein in β cells and has been implicated in β cells' viability and function, however, the role of UCH-L1 in β cells remains unclear. Herein, we examined the functions of UCH-L1 in β cells by utilizing the Drosophila melanogaster model. Our results showed that specific knockdown of dUCH (D.melanogaster homolog of UCH-L1) in Drosophila Insulin-producing cells (D.melanogaster homolog of β cells) induced mitochondria fusion, IPCs death/degeneration, interfered with DILP2 secretion, and triggered the rise of glycogen storage and body weight. Strikingly, the impairment in IPCs cellular activities can be rescued by vitamin C- a strong antioxidant compound, which suggested the relationship between knockdown dUCH and oxidative stress in IPCs; and the potential of this model in screening compounds for β cells function moderation. Since carbohydrate metabolism is an important function of beta cells, we continued to examine the ability to regulate carbohydrate metabolism of knockdown dUCH flies. Our results showed that knockdown dUCH caused the decline of IPCs number under a high-sucrose diet, which finally led to metabolic and physiological disturbances, including total lipid rise, glycogen storage reduction, circulating carbohydrate increase, and weight loss. These symptoms could be early indications of metabolic disorders, particularly β cell dysfunction-related diseases. Taken together, our results indicate that dUCH is essential in the viability and functions of IPCs through the regulation of carbohydrate metabolism in the Drosophila model.