Sugar responsive regulatory network that controls organismal carbohydrate, amino acid and lipid homeostasis [set 2]

Maintaining metabolic homeostasis in response to fluctuating nutrient intake requires intricate coordination between tissues of multicellular animals. The insulin/glucagon axis is well known to hormonally coordinate organism-wide carbohydrate metabolism. The ChREBP/Mondo-Mlx transcription factors regulate glycolytic and lipogenic genes locally in hepatocytes and adipocytes, but its role in systemic metabolic homeostasis has remained poorly understood. We demonstrate that Mondo-Mlx controls gene activity in several peripheral tissues of Drosophila melanogaster, where it regulates nutrient digestion and transport as well as carbohydrate, amino acid and lipid metabolism. In addition to directly regulating metabolic genes Mondo-Mlx controls a regulatory network composed of the Activin ligand Dawdle and GLI similar transcription factor Sugarbabe. Dawdle and Sugarbabe contribute to the regulation of a subset of Mondo-Mlx-dependent processes, including sugar-induced de novo synthesis of serine and fatty acids. In summary, our study establishes Mondo-Mlx sugar sensor as a master regulator of organismal metabolic homeostasis upon sugar feeding. Overall design: Control (sug17d/+) and sugarbabe null mutant (sug17d/sug def) third instar larvae were fed control low sugar or high sugar diet and total RNA was extracted from the whole larvae.

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Mattila J, Havula E, Suominen E, Teesalu M, Surakka I, Hynynen R, Kilpinen H, Väänänen J, Hovatta I, Käkelä R, Ripatti S, Sandmann T, Hietakangas V