NO to Obesity: Does Nitric Oxide Regulate Fat Oxidation and Insulin Sensitivity?

Extract

Nitric oxide (NO) is a free radical gas that acts as a pleiotropic transmitter in many diverse functions (1). Most importantly, its production by endothelial NO synthase (eNOS) mediates vasodilation and inhibits thrombocyte aggregation. In other cells such as immune cells or neurons, NO is produced by the inducible NO synthase (iNOS) and neuronal NO synthase (nNOS), and mediates an inflammatory response or acts as an atypical neurotransmitter, respectively. Furthermore, it was suggested that NO plays an important role in the regulation of energy balance because administration of the nonspecific NO synthase inhibitor N-nitro-l-arginine-methyl ester (L-NAME) reduced weight gain and food intake in mice (2). In nNOS-knockout mice, the appetite-suppressant activity of leptin was markedly reduced, suggesting that NO is a downstream signal of leptin (3). Because deletion of the iNOS protected mice against high-fat diet-associated insulin resistance (4), it was also suggested that NO (“nitrosative stress”) is a player in the pathogenesis of insulin resistance (5). However, such a link between NO and insulin sensitivity is not consistent with studies in eNOS knockout mice, in which deletion of one allele led to reduced insulin sensitivity in response to a high-fat diet (6), and with the concept that endothelial dysfunction is reciprocal to insulin sensitivity (7). Such unresolved inconsistencies may be the reason why NO has not yet made its way into the current textbooks as a major player in the regulation of adiposity and insulin sensitivity or a pathogenetic factor for obesity and diabetes.