Today’s guest post is by Anna Drangowska-Way, PhD, a freelance science writer based in Poland. Anna is working with non-profit organizations, promoting open research practices, and writing about recent scientific discoveries. Connect with Anna on LinkedIn.

Studies show that differences between biological males and females extend far beyond reproductive organs, and affect organisms on many levels across multiple species. 

Those differences include variability in metabolism and disease susceptibility. For example, human females show a significantly higher incidence of severe obesity, making females vulnerable to many comorbidities that occur with obesity, while males have a higher predisposition to diabetes and insulin resistance. At least some of the differences in metabolism can be linked to the different nature of adipose tissue in males and females. While efforts have been made to understand those differences, there remains a great need to elucidate their molecular basis. 

In a recently published study, researchers used the fruit fly Drosophila melanogaster to better understand sex-based differences in gene expression in adipose tissue, which in fruit flies performs both fat and liver-like functions. 

They built on previous studies that observed increased resistance to a variety of stressors in Drosophila females and explored previously understudied avenues, specifically the Integrated Stress Response (ISR) signaling pathway, which acts via the transcription factor ATF4. 

Using various markers and reporters that reflect ATF4 activity, the researchers showed that female larval fat bodies have significantly higher ATF4 activity than those of males. In further experiments that altered adipocytes’ (fat cells) sexual identity by genetically manipulating expression of sexual differentiation genes only in adipocytes, thus masculinizing female adipocytes or feminizing male adipocytes, they showed that sex-dependent differences in ATF4 activity in larval fat body are driven by the sexual identity of those cells (however, the impact of the sexual identity of different cells on ATF4 cannot be excluded).

Among other functions, ATF4 plays a role in nutritional stress. For example, previous research has shown activation of the ISR and induction of ATF4 expression following dietary methionine depletion. However, in those studies, nutrients were depleted in the whole animal. Those researchers used genetic models to specifically deplete methionine in adipocytes. When methionine was depleted in fat tissue during development, males exhibited significantly higher developmental lethality than females, supporting the hypothesis that females are more resistant to fat-body–specific methionine depletion. Later experiments suggested that higher resilience to methionine deprivation in females depends on both the sexual identity of adipocytes and higher ATF4 expression in adipocytes.

This study shows the sex-specific role of the transcription factor ATF4 in fruit fly adipocytes and its contribution to the female-specific increase in resistance to methionine depletion. In a broader context, an understanding of the molecular processes that govern sex-dependent energy metabolism can improve understanding of sex differences in disease susceptibility and progression.

References

  • Grmai L, Mychalczuk M, Arkalgud A, et al. Sexually dimorphic ATF4 expression in the fat confers female stress tolerance in Drosophila melanogaster, GENETICS, 2026, iyag083, https://doi.org/10.1093/genetics/iyag083

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