Time-restricted eating promotes sustained fat loss in Drosophila

While current therapeutics that restrict calorie intake, such as GLP-1 agonists, effectively induce fat loss for many people, they are not effective for others and questions remain about their long-term effects on health, particularly detrimental loss of lean muscle mass. Moreover, many people quickly regain fat if they stop treatment. Time-Restricted Eating (TRE) does not restrict calorie intake but instead restricts the time window for eating and has been shown to prevent obesity in mice and humans. Here we investigated the effects of intermittent Time-Restricted Feeding (iTRF), which is known to delay aging markers and extend lifespan, on stored fat in Drosophila. We found that 10 days of iTRF caused significant fat loss relative to ad lib diet, an effect that persisted even after return to ad lib diet. Unlike iTRF-induced lifespan extension, iTRF-induced fat loss did not depend on circadian-regulated autophagy. iTRF both prevented and treated diet-induced and genetic obesity and significantly reduced lipid droplet size in the fat body (adipose tissue). Instead of causing muscle loss, iTRF increased overall and muscle-specific protein levels and enhanced flight performance, suggesting a shift in body composition. We found that iTRF catalyzed a "fight or flight" response of fasting-induced hyperactivity, mediated by octopamine, the fly ortholog of the human stress hormone norepinephrine. While fasting-induced hyperactivity ("timed exercise") was not sufficient to cause fat loss, ablation of octopaminergic neurons (OANs) prevented iTRF-mediated fat loss, protein gain, and improved flight performance. Furthermore, octopamine itself was both necessary and sufficient for iTRF-mediated fat loss. Taken together, our results suggest that intermittent fasting in Drosophila causes rapid, permanent fat loss by triggering a "fight or flight" response, while increasing muscle function. Further understanding of this response mechanism to intermittent fasting will offer insights into therapeutic interventions for patients with obesity.