View Program - 63rd Annual Drosophila Research Conference

Maintaining carbohydrate homeostasis is essential for organismal health. Insufficient carbohydrates stores results in an inadequate amount of energy to fuel cellular processes. Conversely, excess carbohydrates leads to metabolic diseases such as type II diabetes. We have found that the TGFβ/Activin signaling pathway is required for homeostasis of stored carbohydrates known as glycogen. In Drosophila the TGFβ/Activin signaling family consists of three ligands: Activinβ, Dawdle and Myoglianin. All ligands signal through a single type I receptor, Baboon, however Baboon has three separate splice isoforms that differ in the ligand binding domain. Each ligand signals through a single splice isoform and tissues express a specific splice isoform. Thus, each ligand results in activation of the TGFβ/Activin signaling pathway in a specific subset of tissues. Interestingly, Activinβ is a positive regulator of glycogen storage, whereas Dawdle negatively regulates glycogen stores. This suggests the effect of TGFβ/Activin signaling on glycogen homeostasis depends on the tissue in which the signal is received.
We have found that motorneuron derived Activinβ signals directly to the muscle to positively regulates glycogen storage. Thus, activinβ mutants have low levels of glycogen in muscle. Glycogen levels in activinβ mutants can be partially rescued by inhibiting glycogen phosphorylase (GlyP), which catalyzes the breakdown of glycogen. Despite increased breakdown of glycogen by GlyP, loss of Activinβ does not result in increased glucose levels suggesting that byproducts of glycogen breakdown are being used to fuel another process.
In addition to serving as a positive regulator of glycogen storage in muscle, Activinβ is also a positive regulator of fat body glycogen levels. Intriguingly, Dawdle negatively regulates fat body glycogen storage, highlighting the tissue specific role of TGFβ/Activin signaling in maintaining glycogen homeostasis. Additionally, loss of Activinβ and Dawdle results in differing responses to a high sugar diet. Loss of Activinβ protects animals from carbohydrate accumulation on a high sugar diet, while Dawdle is required for survival on a high sugar diet.

Differential regulation of glycogen homeostasis by TGFβ/Activin ligands