The Impact of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Metabolic Rate in Drosophila melanogaster

Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) may increase metabolic rate by promoting thermogenesis, potentially through enhanced fat oxidation and improved insulin. More research is, however, needed to understand this intricate process. In this study, we used 22 lines from the <i>Drosophila</i> Genetic Reference Panel to assess the metabolic rate of virgin female and male flies that were either fed a standard medium or received lisinopril for one week or five weeks. We demonstrated that lisinopril affects the whole-body metabolic rate in <i>Drosophila melanogaster</i> in a genotype-dependent manner. However, the effects of genotypes are highly context-dependent, being influenced by sex and age. Our findings also suggest that lisinopril may increase the <i>Drosophila</i> metabolic rate via the accumulation of a bradykinin-like peptide, which, in turn, enhances cold tolerance by upregulating <i>Ucp4b</i> and <i>Ucp4c</i> genes. Finally, we showed that knocking down <i>Ance</i>, the ortholog of mammalian ACE in Malpighian/renal tubules and the nervous system, leads to opposite changes in metabolic rate, and that the effect of lisinopril depends on <i>Ance</i> in these systems, but in a sex- and age-specific manner. In conclusion, our results regarding <i>D. melanogaster</i> support existing evidence of a connection between ACEI drugs and metabolic rate while offering new insights into this relationship.