Sex-specific regulation of fat metabolism in Drosophila

Maintaining energy homeostasis is essential for survival in a changing environment. When dietary energy is abundant, animals store excess energy and when dietary energy is scarce, animals mobilize energy stores to support biological functions. In most animals, fat is the main form of stored energy. One important factor that regulates fat metabolism is biological sex. In many animals, females store more fat and have decreased fat breakdown compared with males. Several studies have investigated how sex chromosomes and hormones establish the male-female differences in fat metabolism; however, the metabolic effectors acting downstream of sex chromosomes and hormones are understudied. To better understand the sex-specific regulation of fat metabolism, I used Drosophila as a model to identify metabolic genes and pathways which contribute to sex differences in fat metabolism. In Chapter 2, I identified male-biased regulation of the triglyceride lipase brummer (bmm) and showed how this regulation contributes to the male-female differences in fat storage and breakdown. Further, I found that bmm functions in the neurons and somatic cells of the gonads to influence these sex differences. However, sex-specific regulation of bmm does not fully account for the male-female differences in fat metabolism. Therefore, in Chapter 3, I investigated the role of sex determination gene transformer (tra) in establishing the male-female differences in fat storage and breakdown. I demonstrated that tra establishes the sex difference in fat storage via the sex-specific regulation of the adipokinetic hormone (Akh) signaling pathway, a major lipolytic pathway. In Chapter 4, I explored the role of the Akh pathway in regulating fat breakdown in females and males. Here, I demonstrated that Akh pathway activity post-starvation has differential effects on fat breakdown in females and males. By investigating the role of metabolic effectors in both sexes, I identified sex-limited effects on fat metabolism in both males and females, highlighting the importance of considering both sexes in experimental design and execution. Overall, my work sets the foundation for future studies aimed at identifying conserved mechanisms underlying sex-specific regulation of fat metabolism, and thus allow for a more comprehensive understanding of fat metabolism and metabolic diseases associated with dysregulated fat metabolism.Medicine, Faculty ofGraduat