Misregulation of an Adaptive Metabolic Response Contributes to the Age-Related Disruption of Lipid Homeostasis in Drosophila

• Foxo regulates intestinal lipase expression in response to metabolic adaptation
• Intestinal Foxo activity regulates organismal lipid homeostasis
• Elevated JNK activation in the aging intestine leads to chronic Foxo activation
• Age-related changes in intestinal JNK/Foxo activity disrupt lipid homeostasis

SummaryLoss 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.

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