Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster

Arpan C. Ghosh; Michael B. O’Connor

doi:10.1073/pnas.1319116111

Edited* by Lynn M. Riddiford, Howard Hughes Medical Institute Janelia Farm Research Campus, Ashburn, VA, and approved March 3, 2014 (received for review October 12, 2013)

Significance

Deciphering the systemic signaling mechanisms that modulate metabolic activity has important implications owing to the central role that metabolism plays in regulating organismal adaptability and survival. Here, we show that loss of Drosophila TGF-β/Activin-like ligand Dawdle (Daw) causes major alterations in larval metabolic activity, including accumulation of tricarboxylic acid cycle intermediates, acidification of hemolymph pH, and misregulation of insulin signaling and nuclear-encoded mitochondrial gene expression. These metabolic defects lead to a food-dependent lethality phenotype, suggesting that Daw likely influences environmental adaptability via its modulation of several central metabolic processes. These observations, coupled with previous findings in mammals and Caenorhabditis elegans, highlight a potentially conserved role for TGF-β/Activin signaling in regulating important metabolic processes across the animal kingdom and may have clinical implications.

Abstract

The ability to maintain cellular and physiological metabolic homeostasis is key for the survival of multicellular organisms in changing environmental conditions. However, our understanding of extracellular signaling pathways that modulate metabolic processes remains limited. In this study we show that the Activin-like ligand Dawdle (Daw) is a major regulator of systemic metabolic homeostasis and cellular metabolism in Drosophila. We find that loss of canonical Smad signaling downstream of Daw leads to defects in sugar and systemic pH homeostasis. Although Daw regulates sugar homeostasis by positively influencing insulin release, we find that the effect of Daw on pH balance is independent of its role in insulin signaling and is caused by accumulation of organic acids that are primarily tricarboxylic acid (TCA) cycle intermediates. RNA sequencing reveals that a number of TCA cycle enzymes and nuclear-encoded mitochondrial genes including genes involved in oxidative phosphorylation and β-oxidation are up-regulated in the daw mutants, indicating either a direct or indirect role of Daw in regulating these genes. These findings establish Activin signaling as a major metabolic regulator and uncover a functional link between TGF-β signaling, insulin signaling, and metabolism in Drosophila.

Footnotes

↵¹To whom correspondence should be addressed. E-mail: moconnor{at}umn.edu.

Author contributions: A.C.G. and M.B.O. designed research; A.C.G. performed research; A.C.G. contributed new reagents/analytic tools; A.C.G. analyzed data; and A.C.G. and M.B.O. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
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