Ecdysone-controlled nuclear receptor ERR regulates metabolic homeostasis in the disease vector mosquito Aedes aegypti.

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)—glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)—was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control. Author summary: Following a blood meal in female mosquitoes, carbohydrate and lipid metabolism become activated, aligned with the high demands of reproductive requirements. Concurrently, the estrogen-related receptor (AaERR) mRNA level in Aedes aegypti rises dramatically. We found that AaERR is regulated by 20-hydroxyecdysone (20E), which is the main regulatory hormone during the post blood meal (PBM) reproductive phase. The 20E receptor, ecdysone receptor (EcR), directly binds to the AaERR gene promoter region, activating transcription of this gene. 20E promotes glycolysis and glycogen catabolism, accelerating carbohydrate utilization. AaERR stimulates fatty acid synthesis and leads to lipid accumulation. We confirmed the direct regulatory relationship between AaERR and metabolism-related enzymes. Further investigation revealed that AaERR depletion inhibited the expression of vitellogenin (Vg) in female mosquitoes and disrupted the development of the ovaries, affirming the critical role of AaERR in 20E-dependent metabolism. These findings highlight the essential part AaERR plays in maintaining metabolic homeostasis and promoting normal reproductive development in female mosquitoes. [ABSTRACT FROM AUTHOR]