In this review, we have examined brain ultrastructural remodeling in females of these three models: (i) a DIO model with elevated leptin and leptin receptor resistance with IGT-prediabetes; (ii) a db/db model with elevated leptin and leptin receptor resistance with obesity and T2DM; and (iii) the novel BTBR ob/ob without measurable leptin and with obesity and T2DM. The gene discussed is LEP; the disease is type 2 diabetes mellitus.