Objective To measure the mRNA and protein expression levels of FOS-like antigen 2 (FOSL2) in various tissues of mice with obesity and type 2 diabetic (T2DM), to analyze their associations with insulin resistance and T2DM, and to inform research on the pathogenesis of obesity and T2DM.

Methods Male 6-week-old C57BL/6J mice were randomly assigned to a control, obesity, and T2DM groups. Body mass, blood glucose, glycosylated serum protein (GSP), triglycerides (TG), total cholesterol (TC), blood urea nitrogen (BUN), urinary albumin (UA), and creatinine (Cr) were measured. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed. In addition, fasting serum insulin (FIns) levels were measured by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE), Oil Red O, and Masson stains were performed to evaluate the pathological morphology of various tissues, hepatic steatosis, and renal fibrosis, respectively. FOSL2 protein expression in various tissues was assessed by immunofluorescence and Western blot, and FOSL2 mRNA expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR).

Results (1) Compared with those of the control group, body mass, TC, TG, FPG, FIns, the area under the curve of IPGTT (IPGTT-AUC), and the value for the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were significantly higher in the obesity and T2DM groups. Mice in the T2DM group exhibited significantly higher GSP, the area under the curve of ITT (ITT-AUC), BUN, UA, Cr, and the urinary albumin-to-creatinine ratio (UACR) (all P < 0.05), and significantly lower β-cell function, as assessed by the Homeostatic Model Assessment of Beta-cell function (HOMA-β) (P < 0.05). (2) According to histopathological staining findings, T2DM mice exhibited morphological changes in pancreatic islets, hepatocyte steatosis, and renal fibrosis. Obese mice showed hepatocyte steatosis and adipocyte hypertrophy, but no obvious changes in pancreatic islet morphology or renal fibrosis. (3) qRT-PCR, immunofluorescence, and Western blot showed that, compared with the control group, FOSL2 mRNA and protein expression levels were significantly decreased in the pancreas, liver, skeletal muscle, and adipose tissue of the T2DM and obesity groups (all P < 0.05). However, compared with the obesity and control groups, FOSL2 mRNA and protein expression levels were significantly increased in the kidney tissue of the T2DM group (all P < 0.05). (4) Correlation analysis showed that, in obese and T2DM mice, GSP, FPG, and HOMA-IR were negatively correlated with pancreatic FOSL2 mRNA levels, while HOMA-β was positively correlated with pancreatic FOSL2 mRNA levels. In the kidneys, these correlations were reversed. TG, TC, BUN, UA, Cr, and UACR were negatively correlated with pancreatic FOSL2 mRNA levels and positively correlated with renal FOSL2 mRNA levels (all P < 0.05). (5) Linear regression analysis showed that as pancreatic FOSL2 mRNA levels increased, UACR and HOMA-IR decreased, while HOMA-β increased. In contrast, as renal FOSL2 mRNA levels increased, UACR and HOMA-IR increased, while HOMA-β decreased.

Conclusion The downregulation of FOSL2 in the pancreas, liver, skeletal muscle, and adipose tissue of obese and T2DM mice is associated with insulin resistance and impaired β-cell function. The increased expression of FOSL2 in the kidney tissue of T2DM mice may be associated with renal injury and renal fibrosis.