FOXO-mediated repression of Dicer1 regulates metabolism, stress resistance, and longevity in Drosophila

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 15; p. e2216539120
• Main Authors: Sánchez, Juan A., Ingaramo, María C., Gervé, María P., Thomas, Maria G., Boccaccio, Graciela L., Dekanty, Andrés
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.04.2023
• Subjects: Adipocytes; Adipose tissue; Animals; Binding sites; Biological Sciences; DEAD-box RNA Helicases - metabolism; Depletion; Deprivation; Drosophila; Drosophila - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Fat body; Forkhead protein; Forkhead Transcription Factors - metabolism; Fruit flies; Humans; Insects; Life span; Lipid metabolism; Lipids; Longevity; Longevity - genetics; Metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Nutrient deficiency; Nutrient status; Oxidation resistance; Oxidative metabolism; Oxidative stress; Oxidative Stress - genetics; Physiological responses; Physiology; Ribonuclease III - genetics; Ribonuclease III - metabolism; adipose tissue; dicer-1; miRNA; Drosophila; oxidative stress
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2216539120

The adipose tissue plays a crucial role in metabolism and physiology, affecting animal lifespan and susceptibility to disease. In this study, we present evidence that adipose Dicer1 (Dcr-1), a conserved type III endoribonuclease involved in miRNA processing, plays a crucial role in the regulation of metabolism, stress resistance, and longevity. Our results indicate that the expression of Dcr-1 in murine 3T3L1 adipocytes is responsive to changes in nutrient levels and is subject to tight regulation in the Drosophila fat body, analogous to human adipose and hepatic tissues, under various stress and physiological conditions such as starvation, oxidative stress, and aging. The specific depletion of Dcr-1 in the Drosophila fat body leads to changes in lipid metabolism, enhanced resistance to oxidative and nutritional stress, and is associated with a significant increase in lifespan. Moreover, we provide mechanistic evidence showing that the JNK-activated transcription factor FOXO binds to conserved DNA-binding sites in the dcr-1 promoter, directly repressing its expression in response to nutrient deprivation. Our findings emphasize the importance of FOXO in controlling nutrient responses in the fat body by suppressing Dcr-1 expression. This mechanism coupling nutrient status with miRNA biogenesis represents a novel and previously unappreciated function of the JNK-FOXO axis in physiological responses at the organismal level.