Introduction and Objective: “Diabesity,” the coexistence of obesity and type 2 diabetes, is a major global health problem characterized by systemic insulin resistance (IR) and increased risk of neurodegenerative complications. Although thiazolidinedione (TZD) PPAR-γ agonists improve insulin sensitivity, their clinical use is limited by adverse effects including adipogenesis, weight gain, and cardiovascular risk. We developed Ademaglitazone (ADM), a novel indole-TZD hybrid, and evaluated its insulin-sensitizing, adipogenic, and neuroprotective properties in a diet-induced mouse model of diabesity. Methods: ADM interaction with the PPAR-γ ligand-binding domain was evaluated using molecular docking and molecular dynamics simulations. Insulin-resistant 3T3-L1 adipocytes and HepG2 hepatocytes were treated with ADM or rosiglitazone (10 μM) to evaluate insulin signaling and adipokine expression. In vivo, male CD1 mice with high-fat diet-induced obesity and IR were treated with ADM (30 mg/kg/day), rosiglitazone, or vehicle for 3 weeks. Metabolic parameters, insulin tolerance, circulating lipids, and brain markers of IR-associated neurodegeneration were analyzed. Results: ADM bound PPAR-γ with enhanced ligand-receptor stability compared with rosiglitazone and restored insulin signaling in vitro with minimal adipogenic activity. In obese mice, ADM significantly improved systemic insulin sensitivity without promoting body-weight gain, reduced circulating RBP4 and NEFA levels, enhanced Glut4 translocation in insulin-responsive tissues, and attenuated adipose tissue hypoxia. Notably, improved metabolic control was accompanied by reduced brain tau hyperphosphorylation, indicating neuroprotective effects. Conclusion: These findings identify ADM as a promising next-generation insulin-sensitizer with reduced adipogenic liability and potential benefit against diabesity-associated neurodegeneration. Disclosure M. Mirabelli: None. R. Syed: None. P.R. Yedla: None. F. Brunetti: None. D.P. Foti: None. A. Brunetti: None.
Mirabelli et al. (Sun,) studied this question.