Endothelial dysfunction is characterized by reduction of the bioavailability of nitric oxide (NO), and is associated with metabolic syndrome including, obesity, insulin resistance, hypertension, coronary heart disease, and aging. Because NO plays important roles in mitochondrial biogenesis, we hypothesize that exogenous application of NO may prevent high fat diet (HFD)-induced obesity and insulin resistance by promotion of adipose tissue browning. In the current study, we developed a novel NO releasing nanomatrix gel with natural peptide amphiphiles (PANO). 8 week old male C57BL/6 mice were randomly divided into 2 groups, and then either vehicle (PA) or PANO was subcutaneously injected into brown adipose tissue area every 2 weeks for 11 weeks while the mice were fed HFD. The mice injected with PANO gained less body weight compared to the mice injected with vehicle. PANO injected mice demonstrated improved glucose tolerance and insulin tolerance. Fasting glucose, insulin and leptin levels were lower in the PANO injected mice compared to the vehicle injected mice. Furthermore, the expression of pro-inflammatory genes in epididymal fat tissue was lower, and the expression of uncoupled protein (UCP1) in brown adipose tissue and inguinal adipose tissue was higher in the PANO-injected mice compared to the vehicle injected mice. Thus, the novel nitric oxide releasing nanomatrix gel ameliorated HFD-induced obesity and insulin resistance by promotion of adipose tissue browning. The results suggest that injection of PANO can be a novel therapeutic for obesity and insulin resistance.
G. Ren: None. A.L. Shaw: None. P. Hwang: None. R.C. Millican: None. H. Jun: None. J. Kim: None.
National Institutes of Health (1R01HL125391-01)