Editors' ChoicePhysiology

Evolution of Metabolic Diseases

Science Signaling  15 Dec 2009:
Vol. 2, Issue 101, pp. ec396
DOI: 10.1126/scisignal.2101ec396

Common diseases in humans in which metabolic control is disrupted may reflect an ancient coupling of immune responses to reallocation of energy resources needed to fight infection. This is the conclusion of DiAngelo and colleagues, who studied the primitive innate immune system of Drosophila and its effects on metabolic control through insulin signaling. In the fly, these processes are centralized in the same organ, the fat body, which is not only the main organ for lipid storage but also the organ where response to infection causes the generation of antimicrobial peptides that are released into the circulatory system. The authors found that activation of the receptor Toll, which recognizes components of infectious microorganisms, caused inhibition of insulin signaling. Such an interaction would likely be beneficial to the organism because insulin signaling promotes energy storage and organismal growth, whereas in times of stress caused by infection, energy would be better diverted to inflammatory immune responses. Infection of flies with bacteria caused an inhibition of insulin signaling [measured as phosphorylation of the protein kinase Akt (also called PKB)]. Expression of a constitutively active Toll protein in the fat body inhibited activation of the insulin signaling pathway caused by expression of an activated insulin receptor or by expression of constitutively active phosphatidylinositol 3-kinase, a downstream effector of insulin signaling. The idea that the response to infection diverts energy away from growth and development was supported by experiments showing delayed development and decreased growth of larval animals expressing the activated Toll receptor protein in the fat body. These effects are similar to those of systemically reduced insulin signaling, and decreased activation of Akt indicated a global inhibition of insulin signaling in response to the changes at the fat body. Supplementation of activated Akt at the fat body rescued these changes, indicating that decreased insulin signaling in the fat body leads to the systemic effects on insulin signaling. The authors propose that further analysis of the powerful Drosophila model may provide insights into the interaction of metabolic and inflammatory responses that appear to be at the center of prominent diseases in Western cultures where excessive availability of nutrients is associated with increased inflammation and resistance to insulin signaling in individuals afflicted with diabetes or metabolic syndrome.

J. R. DiAngelo, M. L. Bland, S. Bambina, S. Cherry, M. J. Birnbaum, The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling. Proc. Natl. Acad. Sci. U.S.A. 106, 20853–20858 (2009). [Abstract] [Full Text]