Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues.

The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor γ in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin-receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor α in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice.