Innate Immune Signaling in Drosophila Blocks Insulin Signaling by Uncoupling PI(3,4,5)P3 Production and Akt Activation

Publication date: 6 March 2018
Source:Cell Reports, Volume 22, Issue 10
Author(s): Stephen W. Roth, Moshe D. Bitterman, Morris J. Birnbaum, Michelle L. Bland
In obese adipose tissue, Toll-like receptor signaling in macrophages leads to insulin resistance in adipocytes. Similarly, Toll signaling in the Drosophila larval fat body blocks insulin-dependent growth and nutrient storage. We find that Toll acts cell autonomously to block growth but not PI(3,4,5)P3 production in fat body cells expressing constitutively active PI3K. Fat body Toll signaling blocks whole-animal growth in rictor mutants lacking TORC2 activity, but not in larvae lacking Pdk1. Phosphorylation of Akt on the Pdk1 site, Thr342, is significantly reduced by Toll signaling, and expression of mutant Akt^T342D rescues cell and animal growth, nutrient storage, and viability in animals with active Toll signaling. Altogether, these data show that innate immune signaling blocks insulin signaling at a more distal level than previously appreciated, and they suggest that manipulations affecting the Pdk1 arm of the pathway may have profound effects on insulin sensitivity in inflamed tissues.

Graphical abstract

Teaser

Innate immune signaling through Toll family receptors induces insulin resistance. Roth et al. find that phosphorylation of Akt by Pdk1 is inhibited by Toll signaling in the Drosophila larval fat body. Toll-dependent impairments in fat body cell growth, nutrient storage, and peripheral growth are rescued by mimicking Akt activation loop phosphorylation.


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