Abstract 1656: Attenuation of Diet-Induced Obesity, Hypertension and Insulin Resistance in Vascular Endothelial Endothelin-1 Knockout Mice
Although ET-1 has been shown to be elevated in obesity and insulin resistance, there has been no study that provides the direct evidence of the role of ET-1 in the development of obesity and insulin resistance. To provide the evidence we fed the vascular endothelial cell Endothelin (ET)-1 knockout (VEETKO) mice, which were generated using Cre-lox technology and Tie-2 Cre promoter, and their WT littermates with high-fat diet (HFD)(n=12 each). Following 8 weeks of HFD, WT mice gained significantly more body weights and adipose tissue weights than VEETKO mice (p<0.01). Hepatic lipid deposition, as measured by triglyceride level, was also lower in VEETKO mice (p<0.01). No difference in glucose and insulin levels between the two genotypes when fed a normal chow. In contrast, after 8 weeks of HFD, glucose and insulin levels were markedly lower in VEETKO mice (p<0.05) suggesting that they are more insulin-sensitive than WT mice. In agreement, insulin tolerance test and glucose tolerance test also showed better insulin sensitivity in VEETKO mice (p<0.05 ANOVA). Further, serum level of adiponectin, an insulin-sensitizing hormone, was also significantly higher in VEETKO mice (p<0.05). HF feeding resulted in the slight but significant increase of blood pressure of WT mice, but not in VEETKO mice. Since obesity and insulin resistance are associated with inflammation and macrophage infiltration in white adipose tissue (WAT) and ET-1 also possesses a pro-inflammatory action, we examined macrophage infiltration as one possible mechanism leading to obesity and insulin resistance. Immunohistochemistry of F4/80, a marker of macrophage, revealed that following HFD macrophage infiltration in WAT was intensified in both genotypes, but to a much higher degree in WT mice (p<0.05). These findings indicate that ET-1 plays an essential role in the development of obesity, hypertension and insulin resistance, and ET-1 antagonism may be a potential therapeutic strategy for these conditions.