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Cell Rep. 2013 Sep 26;4(6):1250-61. doi: 10.1016/j.celrep.2013.08.004. Epub 2013 Sep 12.

Misregulation of an adaptive metabolic response contributes to the age-related disruption of lipid homeostasis in Drosophila.

Author information

  • 1Department of Biology, University of Rochester, Rochester, NY 14627, USA; Buck Institute for Research on Aging, Novato, CA 94945, USA. Electronic address: jkarpac@buckinstitute.org.

Abstract

Loss of metabolic homeostasis is a hallmark of aging and is commonly characterized by the deregulation of adaptive signaling interactions that coordinate energy metabolism with dietary changes. The mechanisms driving age-related changes in these adaptive responses remain unclear. Here, we characterize the deregulation of an adaptive metabolic response and the development of metabolic dysfunction in the aging intestine of Drosophila. We find that activation of the insulin-responsive transcription factor Foxo in intestinal enterocytes is required to inhibit the expression of evolutionarily conserved lipases as part of a metabolic response to dietary changes. This adaptive mechanism becomes chronically activated in the aging intestine, mediated by changes in Jun-N-terminal kinase (JNK) signaling. Age-related chronic JNK/Foxo activation in enterocytes is deleterious, leading to sustained repression of intestinal lipase expression and the disruption of lipid homeostasis. Changes in the regulation of Foxo-mediated adaptive responses thus contribute to the age-associated breakdown of metabolic homeostasis.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
24035390
[PubMed - indexed for MEDLINE]
PMCID:
PMC3832190
Free PMC Article

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