Regulation of metabolic homeostasis through sugar 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. We aim to understand how cellular signaling and gene expression is regulated in response to dietary sugars and how these genetic responses influence animal physiology. Tolerance to dietary sugars displays high degree of natural variation, even between closely related species and it is due to genetic changes in genes that control metabolic pathway activities (Melvin et al., 2018).

Our work has mainly focused on the physiological role of Mondo (ChREBP) –Mlx, which is a transcription factor complex mediating intracellular sensing of sugar metabolites. We have discovered that loss of Mondo-Mlx leads to striking sugar intolerance in Drosophila, which suggests that these transcription factors and their targets may be relevant in adjusting the limits of safe sugar utilization (Havula et al., 2013). Mondo-Mlx is a master regulator of a sugar-sensing gene regulatory network, including other transcription factors, such as Cabut (Klf10) and Sugarbabe (GLIS2) (Bartok et al., 2015; Mattila et al., 2015). Mondo-Mlx is also interconnected with hormonal signaling, as it regulates the sugar-inducible expression of TGF-beta/Activin ligand Dawdle (Mattila et al., 2015). Consequently, Mondo-Mlx is contributes to the regulation of the majority of sugar-regulated genes in Drosophila tissues, including genes involved in nutrient transport as well as lipid and amino acid metabolism (Mattila et al., 2015). Genomic variants of human Mondo ortholog ChREBP (MLXIPL) associate strongly with circulating triglyceride levels, which is a cardiometabolic risk factor. The homologs of Drosophila Mondo-Mlx targets are significantly enriched among genes that are in the vicinity of other triglyceride-associated SNPs (Mattila et al., 2015), which highlights the conservation of intracellular sugar sensing in animals. Our current work focuses on new members of the Mondo-Mlx-dependent gene regulatory network, as well as other sugar sensing mechanisms that act in parallel to Mondo-Mlx. We are also exploring whether the mechanisms we have discovered contribute to pathophysiologies in human.