Introduction and Objective: Obesity and type 2 diabetes are associated with mitochondrial dysfunction and reduced plasticity of white adipose tissue (WAT), characterized by impaired adaptive responses to metabolic demands. miR-22 plays a key role in lipid metabolism dysregulation, and its inhibition has been shown to restore metabolic homeostasis in preclinical models. RES-010, a first-in-class antisense oligonucleotide targeting miR-22, is intended to enhance adipose metabolism and energy balance. This study investigates its effects and translational potential in different obesity models.Methods: RES-010 was tested in diet-induced obese (DIO) mice, non-human primates (NHPs) on a fast-food diet (FFD), and two 3D human in vitro models of adipose tissue. Mitochondrial biogenesis and function were assessed via mtDNA quantification and gene expression analysis of key mitochondrial markers. Thermogenic activation was evaluated by ATP content quantification and oxygen respiration, while WAT browning was confirmed through UCP1 expression and morphological analyses.Results: In DIO-mice, RES-010 enhanced mitochondrial biogenesis and promoted WAT browning, leading to improved metabolic parameters. In FFD-NHPs, sub-chronic treatment resulted in upregulation of mitochondrial biogenesis and activation markers, with consistent brownization of WAT, reinforcing the translational potential of RES-010. In human-derived adipose tissue models, RES-010 induced a significant, time-dependent thermogenic effect, as indicated by increased ATP content, and promoted browning, confirmed by increased UCP1 expression, uncoupled oxygen respiration, and structural remodeling.Conclusion: By targeting miR-22, RES-010 reprograms adipose metabolism, promoting mitochondrial activation and WAT browning across obese mice, overweight non-human primates, and human adipose tissue models. These findings suggest that miR-22 inhibition may represent a novel therapeutic strategy to enhance metabolic flexibility.
A. Toniolo: None. A. Altieri: None. A. Nitsche: Employee; Resalis Therapeutics. Stock/Shareholder; Sanofi, Lilly USA LLC. F. Margiotta: None. S. Kauppinen: Consultant; Resalis Therapeutics. R. Panella: None.
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