Transforming Growth Factor ß/Activin signaling in neurons increases susceptibility to starvation.

Animals rely on complex signaling network to mobilize its energy stores during starvation. We have previously shown that the sugar-responsive TGFß/Activin pathway, activated through the TGFß ligand Dawdle, plays a central role in shaping the post-prandial digestive competence in the Drosophila midgut. Nevertheless, little is known about the TGFß/Activin signaling in sugar metabolism beyond the midgut. Here, we address the importance of Dawdle (Daw) after carbohydrate ingestion. We found that Daw expression is coupled to dietary glucose through the evolutionarily conserved Mio-Mlx transcriptional complex. In addition, Daw activates the TGFß/Activin signaling in neuronal populations to regulate triglyceride and glycogen catabolism and energy homeostasis. Loss of those neurons depleted metabolic reserves and rendered flies susceptible to starvation.

Physiological Adaptations to Sugar Intake: New Paradigms from Drosophila melanogaster.

Sugars are important energy sources, but high sugar intake poses a metabolic challenge and leads to diseases. Drosophila melanogaster is a generalist fruit breeder that encounters high levels of dietary sugars in its natural habitat. Consequently, Drosophila displays adaptive responses to dietary sugars, including highly conserved and unique metabolic adaptations not described in mammals. Carbohydrate homeostasis is maintained by a network comprising intracellular energy sensors, transcriptional regulators, and hormonal and neuronal mechanisms that together coordinate animal behavior, gut function, and metabolic flux. Here we give an overview of the physiological responses associated with sugar intake and discuss some of the emerging themes and applications of the Drosophila model in understanding sugar sensing and carbohydrate metabolism.

Transforming growth factor ß/activin signaling functions as a sugar-sensing feedback loop to regulate digestive enzyme expression.

Organisms need to assess their nutritional state and adapt their digestive capacity to the demands for various nutrients. Modulation of digestive enzyme production represents a rational step to regulate nutriment uptake. However, the role of digestion in nutrient homeostasis has been largely neglected. In this study, we analyzed the mechanism underlying glucose repression of digestive enzymes in the adult Drosophila midgut. We demonstrate that glucose represses the expression of many carbohydrases and lipases. Our data reveal that the consumption of nutritious sugars stimulates the secretion of the transforming growth factor ß (TGF-ß) ligand, Dawdle, from the fat body. Dawdle then acts via circulation to activate TGF-ß/Activin signaling in the midgut, culminating in the repression of digestive enzymes that are highly expressed during starvation. Thus, our study not only identifies a mechanism that couples sugar sensing with digestive enzyme expression but points to an important role of TGF-ß/Activin signaling in sugar metabolism.

Sox transcription factors require selective interactions with Oct4 and specific transactivation functions to mediate reprogramming.

The unique ability of Sox2 to cooperate with Oct4 at selective binding sites in the genome is critical for reprogramming somatic cells into induced pluripotent stem cells (iPSCs). We have recently demonstrated that Sox17 can be converted into a reprogramming factor by alteration of a single amino acid (Sox17EK) within its DNA binding HMG domain. Here we expanded this study by introducing analogous mutations to 10 other Sox proteins and interrogated the role of N-and C-termini on the reprogramming efficiency. We found that point-mutated Sox7 and Sox17 can convert human and mouse fibroblasts into iPSCs, but Sox4, Sox5, Sox6, Sox8, Sox9, Sox11, Sox12, Sox13, and Sox18 cannot. Next we studied regions outside the HMG domain and found that the C-terminal transactivation domain of Sox17 and Sox7 enhances the potency of Sox2 in iPSC assays and confers weak reprogramming potential to the otherwise inactive Sox4EK and Sox18EK proteins. These results suggest that the glutamate (E) to lysine (K) mutation in the HMG domain is necessary but insufficient to swap the function of Sox factors. Moreover, the HMG domain alone fused to the VP16 transactivation domain is able to induce reprogramming, albeit at low efficiency. By molecular dissection of the C-terminus of Sox17, we found that the ß-catenin interaction region contributes to the enhanced reprogramming efficiency of Sox17EK. To mechanistically understand the enhanced reprogramming potential of Sox17EK, we analyzed ChIP-sequencing and expression data and identified a subset of candidate genes specifically regulated by Sox17EK and not by Sox2.