Title : Sex-Specific Metabolic Reprogramming by Nanoemulsified Policosanol-Simvastatin Combinations: Synergistic Regulation of the IIS Pathway and BMM-Mediated Lipolysis in a Drosophila Model of Metabolic Syndrome
Abstract:
Background: Cardiovascular diseases (CVDs) and metabolic syndrome (MetS) exhibit profound sexual dimorphism, yet many pharmacological interventions remain non-specific. While statins are the gold standard for dyslipidemia, suboptimal efficacy and side effects necessitate precision combinatorial approaches.
Objective: This study investigates the mechanistic efficacy of nanoemulsified Simvastatin (SIM) and Policosanol (POL) combinations in reprogramming the Insulin/IGF-1 Signaling (IIS) pathway and lipid mobilization in Drosophila melanogaster.
Methods: Nanoemulsions were synthesized using high- and low-energy methods, and administered to a High-Fat, High-Sugar (HFHS) induced MetS model. We utilized biochemical profiling, gene expression analysis of the BMM-FOXO-AKH axis, and Combenefit-based Loewe additivity modeling to assess sex-specific synergy.
Results: Nanoemulsions were stable with particle sizes <200 nm (29.86 nm to 121.9 nm) and Polydispersity Index (PDI) values between 0.283 and 0.463. In both sexes, treatments significantly (p < 0.001) reversed HFHS-induced hyperglycemia and hyperlipidemia. Notably, males exhibited synergy in glucose control (T7, T9) through a "catabolic switch" involving massive upregulation of AKH and FOXO. Conversely, females showed high sensitivity in ILP2 signaling and synergistic lipid modulation (T7, T8) driven by widespread BMM lipase upregulation.
Conclusion: Nanoemulsified POL-SIM combinations effectively modulate lipid and carbohydrate metabolism by regulating the Insulin/IGF-1 Signaling (IIS) pathway. This highlights a promising precision-medicine framework for CVD prevention.
Keywords: Drosophila melanogaster, Insulin/IGF-1 Signaling (IIS) pathway, nanoemulsion, Policosanol, Simvastatin, Metabolic Syndrome, Sexual dimorphism, Cardiovascular diseases
