A novel role of adipose AMPK-p53 axis in systemically regulating insulin signaling and autophagy
The tumor suppressor p53 has been shown to regulate energy metabolism through multiple mechanisms. However, signaling pathways associated to in vivo regulation of metabolism by p53 and its possible role in inter-organ communication under nutrient stress remain largely uncharacterized. By using Drosophila as a model organism we show that AMPK-dependent Dmp53 activation is critical for sensing nutrient stress, maintaining metabolic homeostasis and extending organismal survival. Dmp53 activation in the adipose tissue remotely control Dilp2 secretion in insulin producing cells under both nutrient deprivation and high caloric diet, through regulation of Drosophila Leptin homolog, Unpaired-2, an insulinotrophic peptide, in adipose cells.  Dmp53 depletion in adipose tissue resulted in increased Dilp2 circulating levels, sustained systemic insulin signaling and repression of autophagy induction in peripheral tissues, thus compromising organismal survival to nutrient stress. These results indicate that Dmp53 plays a novel and essential role in Drosophila integrating nutrient status with metabolic and physiological responses by modulating Dilp2 circulating levels, systemic insulin signaling and autophagy.