The sole Drosophila melanogaster insulin receptor gene mediates metabolism and movement regulating lipid and carbohydrate stores, sleep, and motor activity.

The insulin signaling pathway is a core and evolutionarily conserved signal transduction network. Here we study hypomorphic mutant conditions in the sole insulin receptor gene (Inr) in the fruit fly Drosophila melanogaster, placed at the beginning of the signaling cascade where it mediates the effects from the seven Drosophila insulin-like peptides. As such, it sits at a nodal point where signaling must pass to ensure and carry out all the functions ascribed to this anabolic pathway. We find that these mutant flies, while viable, exhibit hyperactivity and accumulate glycogen and body lipids. The hyperactivity phenotype was characterized in detail and is significantly different from controls both measuring it in several days' spells, or when done in a more detailed fashion in shorter time periods (twenty-five minutes). The proportion of time spent sleeping is also altered, highlighting the robust role that the insulin pathway has not only regulating metabolism but also behavior. When confronted with mild pro-oxidative conditions, these flies and control wildtype flies have reduced lifespans as well. The metabolic dysregulation is rescued when the Inr mutant flies are also heterozygous for keap1, a negative regulator of the Nrf2 pathway, while the antioxidant response and the activity/sleep levels exhibit only partial and sexually dimorphic improvements. Transcriptomic analyses of Inr mutants show that many metabolism and hormonal signaling genes are dysregulated.