2616-P: Leptin Pathway Dysregulation in African Americans with Type 2 Diabetes

Introduction and Objective: Leptin (LEP), an adipocyte-derived hormone, plays a central role in energy homeostasis and insulin sensitivity. Dysregulation of LEP signaling has been connected to obesity associated T2D; however, population-specific molecular evidence in African Americans (AAs) remains limited. We aimed to characterize LEP-associated transcriptional alterations and pathway dysregulation in AA adults with T2D from the DC area. Methods: Whole-blood RNA sequencing was performed on 34 AA participants recruited from the Diabetes Center, including T2D (n=23) and non-T2D controls (n=11). The sociodemographic, lifestyle, and medical histories were recorded. Differential gene expression analysis was conducted using Illumina sequencing, followed by Ingenuity Pathway Analysis to identify LEP-related signaling networks. Results: LEP (FC= -1.65) expression was significantly downregulated in T2D compared to controls. Pathway analysis revealed disrupted LEPR-mediated signaling in hypothalamic NPY/AgRP and POMC neuronal pathways, characterized by SOCS3 upregulation and inhibition of JAK-STAT signaling. This suppression promoted persistent nuclear FOXO1 activity, increased orexigenic NPY/AgRP expression, impaired appetite suppression, and features consistent with leptin resistance. Conclusion: These findings demonstrate LEP pathway dysregulation at the transcriptomic level in AAs with T2D, providing mechanistic insight into leptin resistance and metabolic dysfunction.