Non-nutritive sweeteners like sucralose are consumed by billions of people. While
animal and human studies have demonstrated a link between synthetic sweetener consumption
and metabolic dysregulation, the mechanisms responsible remain unknown. Here we use
a diet supplemented with sucralose to investigate the long-term effects of sweet/energy
imbalance. In flies, chronic sweet/energy imbalance promoted hyperactivity, insomnia,
glucose intolerance, enhanced sweet taste perception, and a sustained increase in food
and calories consumed, effects that are reversed upon sucralose removal. Mechanistically,
this response was mapped to the ancient insulin, catecholamine, and NPF/NPY systems
and the energy sensor AMPK, which together comprise a novel neuronal starvation response
pathway. Interestingly, chronic sweet/energy imbalance promoted increased food intake
in mammals as well, and this also occurs through an NPY-dependent mechanism. Together,
our data show that chronic consumption of a sweet/energy imbalanced diet triggers
a conserved neuronal fasting response and increases the motivation to eat.