Fat Body p53 Regulates Systemic Insulin Signaling and Autophagy Under Nutrient Stress via Drosophila Upd2 Repression

Abstract

The tumor suppressor p53 regulates multiple metabolic pathways at the cellular level. However, the molecular mechanisms underlying the regulation of p53 in vivo in response to metabolic perturbations as well as its possible role in inter-organ communication remain largely uncharacterized. Using Drosophila, we show that AMPK-dependent Dmp53 activation is critical for sensing nutrient stress, maintaining metabolic homeostasis and extending organismal survival. Under both nutrient deprivation and high-sugar diet, Dmp53 activation in the fat body (functional analog of vertebrate adipose and hepatic tissues) remotely controls Dilp2 secretion in insulin producing cells (IPCs) through repression of the Drosophila Leptin homolog, Unpaired-2 (Upd2). Elevated Upd2 expression in adipose cells and subsequent activation of Upd2 receptor Domeless in the brain of starved Dmp53-depleted animals result in sustained Dilp2 circulating levels, activation of insulin signaling and impaired autophagy induction, therefore reducing survival rates upon nutrient deprivation. Our results demonstrate a novel and essential role for AMPK-Dmp53 axis in Drosophila fat body integrating nutrient status with metabolic and physiological responses.