Transforming Growth Factor beta/Activin Signaling Functions as a Sugar-Sensing Feedback Loop to Regulate Digestive Enzyme Expression

Maroun Bou Sleiman, Wen Bin Chng, Bruno Lemaitre
Elsevier, 2014
Journal paper

Abstract

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 beta (TGF-beta) ligand, Dawdle, from the fat body. Dawdle then acts via circulation to activate TGF-beta/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-beta/Activin signaling in sugar metabolism.

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Multicellular organisms assess their nutritional state and adapt their metabolic landscape to match their energy demands. In this thesis, we address a longstanding conundrum of how an organism coordinates digestive enzyme expression in response to its nutritional status. Hydrolysis of food materials by endogenous or microbial-derived digestive enzymes precedes absorption through the gut lumen. Thus, modulation of endogenous digestive mechanism represents a pragmatic step to limit the uptake of nutrients when nutrients are in abundance. In Drosophila melanogaster, it is known that dietary glucose represses amylase transcript and enzymatic activity, in a process known as glucose repression. Here, we show that glucose reduces the expression of many carbohydrases, lipases, and glucose transporters, presumably to prevent nutritional overload after feeding. We found that the repression of carbohydrases is effected by nutritious sugars through the induction of the TGF-beta ligand, Dawdle. Interestingly, glucose repression of digestive enzymes is dependent upon the induction of Dawdle in the fat body, a tissue functionally analogous to the mammalian liver and adipose tissue. Dawdle is then transported via the circulation to activate TGFÎ²/Activin signaling in the midgut, leading to the repression of digestive enzymes expression. We later discovered that Dawdle expression in the fat body is regulated by the evolutionarily conserved Mio-bigmax transcription factor complex. In addition, expression of Dawdle must be tightly coordinated to reflect the nutritional state of adult flies, as flies overexpressing Dawdle are sensitive to starvation and have their TAG and glycogen stores rapidly depleted upon nutrient limitation. Thus, our results are consistent with a model whereby fat body derived Daw functions as a nutritional cue for carbohydrates to modulate metabolic responses in distal tissues. Its induction provides the nutritional signal to repress carbohydrate digestive capacity and stimulate peripheral insulin signaling. In conclusion, our study identifies the TGFÎ²/Activin signaling as a critical mechanism for carbohydrate homeostasis. Our results indicate that the fat body functions as a carbohydrate sensing tissue, which through the secretion of the TGFÎ² ligand, Daw, regulates organism-wide carbohydrate metabolism. Our work in Drosophila is likely to have a broader scientific impact by placing a pathway known for its role in development, immunity, and cancer, as an integral component for sugar sensing and metabolism.

EPFL2015

, ,

Animals rely on complex signaling network to mobilize its energy stores during starvation. We have previously shown that the sugar-responsive TGF beta/Activin pathway, activated through the TGF beta ligand Dawdle, plays a central role in shaping the post-prandial digestive competence in the Drosophila midgut. Nevertheless, little is known about the TGF beta/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 TGF beta/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.

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Public Library of Science2017

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