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 melanogast er model. Our results showed that specific knockdown of dUCH (D.melanogast er homolog of UCH-L1) in Drosophila Insulin-producing cells (D.melanogast er 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. Knockdown of dUCH in Drosophila insulin-producing cells (IPCs) decreased the number of IPCs and interfered in DILP2 secretion into the hemolymph. The knockdown of dUCH in IPCs induced oxidative stress and abnormal mitochondrial morphology thereby consequently resulted in the death/degeneration of IPCs. The result revealed for the first time a curial roles of dUCH in mitochondrial morphology and activities in IPCs Knockdown of dUCH in IPCs induced irregular carbonhydrate metabolism in Drosophila model Combination of dUCH knockdown and high sugar diet exacerbated IPCs degeneration or carbohydrate and lipid homeostasis There is synergistic effect of the dUCH knockdown and high sucrose concentration on mitochondria of IPCs [ABSTRACT FROM AUTHOR]