A novel free fatty acid receptor agonist improving metabolic health in Drosophila models.

The development of synthetic modulators for human free fatty acid receptors (FFARs) has gained attention for addressing diabetes, metabolic syndrome, and dyslipidaemia. A new dual FFAR1 (GPR40) and FFAR4 (GPR120) agonist, DFL23916, was recently identified to improve glucose homeostasis, prompting investigations into its effects on metabolic disorders. This study assessed the selectivity and toxicity of DFL23916 in vitro and evaluated its effects in vivo using Drosophila melanogaster models of high-sugar (HSD) and high-fat diets (HFD). DFL23916 showed no off-target activities with no toxicity/hepatotoxicity in cultured cells. In adult HSD-fed flies with defective mobility, the oral administration of DFL23916 enhanced climbing speed in a concentration-dependent manner and reduced the high content of glucose and triglyceride levels alongside markers of insulin resistance. The compound did not affect viability and food intake of flies exposed to chronic overcaloric conditions but it inhibited the progressive weight gain. Similarly, larvae development remained unaffected by DFL23916, while it counteracted glucose and triglyceride elevation and reduced lipid droplet size caused by HSD and HFD. Finally, in silico analysis highlighted the relevance of evolutionary conserved Drosophila receptors in fatty acid sensing, suggesting putative candidates for DFL23916 binding. Collectively, these findings indicated the safe profile of DFL23916 and its efficacy in ameliorating hyperglycaemic and hyperlipidaemic features in overcaloric fed flies. Our results not only suggest that DFL23916 could be a potential candidate for further investigation in the context of metabolic disorders but also reinforce D. melanogaster as a valuable model for the preclinical evaluation of metabolic interventions, including FFAR-targeting strategies.