Final Report Summary - GLUCOSE SENSING (Transcriptional networks in glucose sensing)
Sugars are highly energetic macronutrients and an essential part of diet for many animals. Excessive consumption of dietary sugars has been associated with increased risk for metabolic diseases in human. However, the genetic determinants that define the range of tolerated sugar intake and the individual's risk for metabolic disturbance on high sugar diet are poorly understood. Nutrient sensing pathways are needed to readjust metabolic pathways in response to changes in nutrient intake. The goal of this project was to understand gene regulatory mechanisms involved in sensing of diet-derived sugars in animals and uncover their physiological role. We have discovered that intracellular sugar sensing transcription factors Mondo-Mlx are key regulators of metabolic homeostasis in response to sugar feeding. A genome-wide analysis of Mondo-Mlx targets have shown that it is responsible for the regulation of a majority of sugar-regulated genes in Drosophila, controlling metabolic gene expression in multiple tissues, including fat body (counterpart of liver and adipose tissue), gut and renal tubules. In addition of metabolic targets, our work has revealed that Mondo-Mlx is a master regulator of a sugar-sensing regulatory network, including other transcription factors, such as Cabut (Klf10) and Sugarbabe (Gli similar). Mondo-Mlx is also interconnected with hormonal signaling, as it regulates the sugar-inducible expression of TGF-beta/Activin ligand Dawdle. Loss of Mondo-Mlx and many of its downstream effectors leads to striking sugar intolerance in Drosophila. In addition to metabolic pathway activities, redox balance needs to be closely controlled in response to sugar feeding. Our recent work has shown that a key regulator of NADPH redox balance is protein kinase SIK3. SIK3 phosphorylates the rate-limiting enzyme of the pentose-phosphate pathway, which maintains NADPH redox balance. Loss of SIK3 leads to oxidative stress on high sugar diet and loss of sugar tolerance. Interestingly, SIK3 converges with Mondo-Mlx to maintain sugar tolerance, as Mondo-Mlx promotes the pentose phosphate pathway transcriptionally. In conclusion, our work has uncovered novel genes involved in dietary sugar sensing in animals and elucidated their physiological roles and functional interrelationships. Our work has opened several new research avenues, both related to basic understanding of animal metabolic control as well as human disease.