Sexually dimorphic ATF4 expression in the fat confers female stress tolerance in Drosophila melanogaster

Metabolic differences between males and females have been well documented across many species. However, the molecular basis of these differences and how they impact tolerance to nutrient deprivation is still under investigation. In this work, we use Drosophila melanogaster to demonstrate that sex-specific differences in fat tissue metabolism are driven, in part, by dimorphic expression of the Integrated Stress Response (ISR) transcription factor, ATF4. We found that female fat tissues have higher ATF4 activity than their male counterparts under homeostatic conditions. This dimorphism was partly due to a female bias in transcript abundance of specific ATF4 splice isoforms. We found that the canonical sex determinants transformer (tra) and doublesex (dsx) drive such dimorphic ATF4 transcript abundance. These differences persist in a genetic model of methionine deprivation stress, where female animals showed greater resistance to lethality than males in an ATF4-dependent manner. These results suggest that higher ATF4 activity confers higher tolerance to stress in females. Together, our data describe a previously unknown facet of ISR signaling wherein sexual identity of adipose tissue confers differential stress tolerance in males and females. Since energy storage mechanisms are known to be dimorphic and have been linked to ATF4 regulation, our studies provide a mechanistic starting point for understanding how sexual identity influences metabolic disease outcomes.