FOXO-mediated Repression of Dicer-1 Regulates Metabolism, Stress Resistance and Longevity in Drosophila

JUAN ANDRES SÁNCHEZ; MARIA C INGARAMO; PAULA GERVE; M. G. THOMAS,; BOCCACCIO G.L.; ANDRES DEKANTY,

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 2023

0027-8424

The adipose tissue plays an essential role in metabolism and physiology which impacts on animal lifespan and disease susceptibility. Here we provide evidence that Dicer-1 (Dcr-1), a conserved type III endoribonuclease involved in miRNA processing, plays an essential role in the Drosophila fat body, analog of vertebrate adipose and hepatic tissues, in regulating metabolism, stress resistance and longevity. Dcr-1 expression is tightly regulated in the fat body under different stress types and physiological conditions including starvation, oxidative stress and aging. In particular, nutrient-dependent regulation of Dcr-1 levels was also observed in murine 3T3L1 adipocytes. Fat body-specific depletion of Dcr-1 resulted in altered lipid metabolism and increased resistance to oxidative and nutritional stress, while a substantial extension in lifespan was observed in Dcr-1 heterozygous mutants. We also provide mechanistic evidence showing that the transcription factor FOXO regulates Dcr-1 expression upon nutrient deprivation. Under these conditions, JNK-dependent activation of FOXO in the fat body is required for the repression of Dcr-1 expression and miRNA biogenesis. Interestingly, FOXO binds to a conserved DNA binding site in the Dcr-1 promoter thus directly repressing its transcription. The mechanism described here coupling FOXO activation in the adipose tissue to the repression of Dcr-1 implicates a novel and previously uncharacterized function for the JNK-FOXO axis integrating nutrient status with miRNA biogenesis and physiological responses at the organismal level.