Gatto, J. A. | Search bioRxiv

bioRxiv2026

Time-restricted eating promotes sustained fat loss in Drosophila

While current therapeutics restricting calorie intake, such as GLP-1 agonists, induce fat loss for many people, they are ineffective for others and concerns remain about their long-term effects on health, particularly loss of lean muscle mass. Moreover, many quickly regain fat if they stop treatment. In contrast, time-restricted eating does not restrict calorie intake but instead restricts the time window for eating and prevents obesity in mice and humans. Here we investigated the effects of intermittent Time-Restricted Feeding (iTRF), which extends lifespan and delays markers of aging, on stored fat in Drosophila. Ten 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 treated both diet-induced and genetically induced obesity and significantly reduced lipid droplet size in the fat body (adipose tissue). Instead of causing muscle loss, iTRF increased total and muscle-specific protein levels and enhanced flight performance, suggesting a shift in body composition. We found that iTRF evoked fasting-induced hyperactivity, partially mediated by octopamine, the fly ortholog of the human stress hormone norepinephrine. Ablation of octopaminergic neurons (OANs) prevented iTRF-mediated effects: fat loss, increased protein, and enhanced flight performance. Our results suggest that Drosophila iTRF causes rapid, permanent fat loss and increased muscle function through a "fight or flight" response. Understanding the mechanisms driving differences between Drosophila and human responses to TRE could be critical for identifying effective therapeutic targets for obesity.

physiology↗

bioRxiv2024

Investigating the consequences of chronic short sleep for metabolism and survival of oxidative stress

In previous work, we found that short sleep caused sensitivity to oxidative stress; here we set out to characterize the physiological state of a diverse group of chronically short-sleeping mutants during hyperoxia as an acute oxidative stress. Using RNA-sequencing analysis, we found that short-sleeping mutants had a normal transcriptional oxidative stress response relative to controls. In both short-sleeping mutants and controls, hyperoxia led to downregulation of glycolytic genes and upregulation of genes involved in fatty acid metabolism, reminiscent of metabolic shifts during sleep. We hypothesized that short-sleeping mutants may be sensitive to hyperoxia because of defects in metabolism. Consistent with this, short-sleeping mutants were sensitive to starvation. Using metabolomics, we identified a pattern of low levels of long chain fatty acids and lysophospholipids in short-sleeping mutants relative to controls during hyperoxia, suggesting a defect in lipid metabolism. Though short-sleeping mutants did not have common defects in many aspects of lipid metabolism (basal fat stores, usage kinetics during hyperoxia, respiration rates, and cuticular hydrocarbon profiles), they were all sensitive to dehydration, suggesting a general defect in cuticular hydrocarbons, which protect against dehydration. To test the bi-directionality of sleep and lipid metabolism, we tested flies with both diet-induced obesity and genetic obesity. Flies with diet-induced obesity had no sleep or oxidative stress phenotype; in contrast, the lipid metabolic mutant, brummer, slept significantly more than controls but was sensitive to oxidative stress. Previously, all short sleepers tested were sensitive and all long sleepers resistant to oxidative stress. brummer mutants, the first exceptions to this rule, lack a key enzyme required to mobilize fat stores, suggesting that a defect in accessing lipid stores can cause sensitivity to oxidative stress. Taken together, we found that short-sleeping mutants have many phenotypes in common: sensitivity to oxidative stress, starvation, dehydration, and defects in lipid metabolites. These results argue against a specific role for sleep as an antioxidant and suggest the possibility that lipid metabolic defects underlie the sensitivity to oxidative stress of short-sleeping mutants.

physiology↗