Myeloperoxidase: A Therapeutic Target for Preventing Insulin Resistance and the Metabolic Sequelae of Obesity?

Many lines of evidence indicate that insulin resistance is a key component of the metabolic syndrome, a cluster of cardiovascular risk factors comprising glucose intolerance, dyslipidemia, hypertension, and obesity (1).Insulin resistance is also of central importance in the pathogenesis of type 2 diabetes, another major risk factor for atherosclerosis (1).However, the molecular mechanisms that precede the development of insulin resistance are only partially understood.Given the dramatic increases in the incidence of obesity and diabetes worldwide, the need to identify new therapies that might protect humans from the metabolic consequences of obesity and insulin resistance is urgent.Macrophages, T cells, B cells, mast cells, and eosinophils accumulate in adipose tissue of obese mice.Each of these immune cells seems to contribute to the development of insulin resistance during diet-induced obesity (2).However, neutrophils-the most abundant circulating immune cell in both mice and humans-are generally the first cells to respond to an inflammatory challenge, although their role in insulin resistance has received much less attention.It is noteworthy that circulating neutrophil concentrations increase in obese mice (3).Moreover, neutrophils accumulate in murine adipose tissue after only 3 days of fat feeding (4).Importantly, recent studies have shown that fat-fed mice that are deficient in neutrophil elastase exhibit less adipose tissue inflammation and are more insulin sensitive than fat-fed controls.These observations suggest that inflammatory mediators derived from neutrophils might promote the development of obesity and its metabolic consequences (5).