862-P: Notch Signaling Inhibitor ADPO-002 Upregulates UCP1 Expression in Mice and Human Adipose Tissue Explants

• Published in: Diabetes (New York, N.Y.) Vol. 74; no. Supplement_1; p. 1
• Main Authors: RAISUL ABEDIN, MUHAMMAD, GAMAL BENKATO, KHEIRIA, OSWALT, MALLORY A., CRAWFORD, CHRISTOPHER B., CONSIDINE, ROBERT V., DENG, MENG
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2025
• Subjects: Adipose tissue; Body fat; Diabetes mellitus (non-insulin dependent); Explants; Gastrointestinal surgery; Gene expression; Nanoparticles; Obesity; Phenotypes; Polylactide-co-glycolide; Protein expression; Proteins; Secretase; Statistics
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db25-862-P

Introduction and Objective: Brown fat in humans has been associated with a lower risk of obesity and type 2 diabetes. This study investigated the regulation of browning marker UCP1 by a novel γ-secretase inhibitor ADPO-002 in mice in vivo, and in adipose tissue excised from humans with obesity. Methods: Lyophilized PLGA nanoparticles (NP; ~4.5% ADPO-002 w/w, 0.2 and 1 mg) and blank NPs were injected into inguinal white adipose tissue (iWAT) of C57BL/6J mice (N=3/group). After 7 days, iWAT was collected for histology, RNA isolation, and UCP1 mRNA quantification by RT-qPCR (statistics: ANOVA). For the human explant study, adipose tissue was collected from 10 bariatric surgery patients (3 men and 7 women, BMI 41.4±11.5 kg/m2). These tissue samples were cultured and treated with DMSO or 30 µM ADPO-002. The tissue was homogenized after 7 days, and UCP1 expression was quantified via ELISA (ng UCP1/mg total protein, statistics: Wilcoxon paired t test). Results: In mice, 0.2 and 1 mg ADPO-002 NP up-regulated UCP1 mRNA expression by 23-fold (p=0.4387) and 109-fold (p=0.0043), respectively compared to the control group. The browning phenotype was further confirmed by H&E staining. In human omental adipose tissue samples treated with 30 µM ADPO-002 (N=10 subjects) UCP1 protein expression significantly increased compared to the DMSO control (5.8±1.1 vs 3.1±0.7 ng/mg, p=0.0098). In human subcutaneous adipose tissue samples treated with 30 µM ADPO-002 (N=8 subjects) there was a trend for UCP1 protein expression to increase compared to the DMSO control (6.3±1.5 vs 3.8±0.8 ng/mg; p= 0.1094). Conclusion: The results suggest that ADPO-002 has a promising browning effect on mice iWAT and human subcutaneous and omental adipose tissue.