Spontaneous Diabetic FATZO Mice with Intact Leptin Signaling Develop Peripheral Immune Cell Responses Similar to T2D and Obese Patients

Introduction: Type 2 diabetes (T2D) and obesity are strongly associated with peripheral immune cell responses. Subsets of T cells in the circulation are correlated with the severity of the diseases, which may serve as novel targets for antidiabetic or obese treatment. Higher numbers of blood Th1, Th17 and Th22 cells of T helper cells were found in disease patients, while Th2 and Treg cells were in reverse correlation of the severity of the disease. FATZO mouse is a new generation of T2D mouse model with intact leptin signaling. The model is featured with slow onset of diabetes and obesity. Here, we aim to characterize the peripheral immune cell responses in FATZO mice for the use of preclinical drug development targeting diabetes or obesity related inflammation. Methods: Freshly collected blood from 12 FATZO mice at age 6, 12, 22 and 34 weeks were analyzed for the presence of monocytes, B, T, NK, NK-T, CD4+, CD8+ T cells and subsets of T helper cells (Th1, Th2, Th17, Th22, Treg) using FACS. Serum inflammatory cytokines such as IL1, IL2, IL6, IL17, TNFα and IFNγ were also measured. Results: FATZO mice developed obesity and hyperglycemia from age of 12 weeks. Concomitantly, higher numbers of leukocytes were noticed with an increase and decrease in frequency of B and NK cells respectively. Within T cells, numbers of CD4+ T cells decreased by 20%, while CD8+ T cells increased by 25%. When subsets of T helper cells were assessed, percentages of Th1 and Th17 cells significantly elevated during the development of diabetes and obesity, while frequencies of Th2 and Treg cells declined. Serum inflammatory cytokine measurements showed a tendency in higher levels of serum IL1a when the animals became diabetic. Conclusion: FATZO mice develop diabetes and obesity with changes in blood immune cell responses that closely mimic disease patients. The results suggest that FATZO might serve as an ideal model for preclinical research for the diabetes and obesity related inflammation. Disclosure G. Sun: None. W. Ye: Employee; Spouse/Partner; Crown Bioscience Inc.. X. An: None. Y. Xiao: None. Y. Wang: None.