Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant conflicts of interest.
Talukdar S, Oh DY , Bandyopadhyay G, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18:1407-1412.
The consultative hematologist is occasionally asked to assess a minimally elevated white blood cell (WBC) count. After a careful history, physical, and a review of the blood film and other laboratory studies, the hematologist concludes that this elevation is not due to underlying marrow pathology but rather reflects ongoing, low-grade inflammation. Innocent enough? Maybe not. An elevated WBC count is a risk factor for atherosclerotic disease. Several prospective studies have shown an independent association between an above- normal WBC and coronary disease or mortality. Elevated WBC is associated with other risk factors, such as smoking and fasting glucose or insulin levels, and inversely related to physical activity, plasma HDL concentration, and family income.1 Inflammation underlies the pathophysiology of non-alcoholic steatohepatitis, which is associated with the metabolic syndrome of obesity, diabetes, hyperlipidemia, and cardiovascular disease.2 The WBC count is elevated in obese patients and in patients with impaired glucose tolerance.3 Although most studies have focused on the role of the WBCs in atherosclerotic vascular injury, the experiments of Talukdar and colleagues in the laboratory of Jerrold Olefsky at the University of California, San Diego, suggest a novel mechanism by which WBCs contribute to cardiovascular disease by participating in inflammation-induced disorders of metabolism. They show that, as a consequence of elastase secreted by WBCs, chronic inflammation induces insulin resistance in mice fed a high-fat diet.
Feeding mice a high-fat diet induced obesity and caused a 20- fold increase in infiltrating neutrophils in adipose tissue that was associated with a marked increase in neutrophil elastase release. Notably, mice treated with a neutrophil elastase inhibitor showed improved glucose tolerance, while treatment with recombinant elastase led to markedly greater glucose intolerance. Additional experiments by Talukdar and colleagues indicated that the proinflammatory effects are mediated, at least in part, by direct activation of Toll-like receptor 4 by neutrophil elastase. When compared with wild-type littermates, neutrophil elastase-knockout mice fed a high-fat diet gained less weight, had fewer infiltrating neutrophils, and had better glucose tolerance and greater insulin sensitivity. mRNA levels of liver lipogenic and cholesterol synthesis genes were also lower in the knockout mice.
This study shows a higher neutrophil content in the liver and adipose tissue of diet-induced obese mice. Since inflammation is characteristic of obesity, the authors conclude that neutrophil elastase may contribute to cellular insulin resistance. This concept was supported by the observation that inhibiting elastase improved insulin resistance and possibly reduced chemokine production.
Do these studies shed light on how elevated WBC counts increase cardiovascular and stroke risk? Possibly. By providing an inflammation connection to insulin resistance, hyperglycemia, and activation of genes associated with atherogenesis, the authors suggest that neutrophils, particularly neutrophil elastase, promote the metabolic syndrome. Would inhibition of elastase be helpful? More than 40 years ago, studies in chronic obstructive pulmonary disease proposed that inactivation of the elastase inhibitor α-1-anti-trypsin by oxidants promoted elastin degradation in the lung. Additional preclinical and clinical studies will be required to determine if antioxidants, omega-3 fatty acids, diet, iron chelation, and protease inhibitors have a role in amelioration of the obesity-related metabolic syndrome. For now, we should remain vigilant pathophysiologists and recognize that inflammation is not always innocent.
1. Lee CD, Folsom AR, Nieto FJ, et al. White blood cell count and incidence of coronary heart disease and ischemic stroke and mortality from cardiovascular disease in African-American and white men and women: atherosclerosis risk in communities study. Am J Epidemiol. 2001;154:758-764.
2. Targher G, Day CP, and Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341-1350.
3. Veronelli A, Laneri M, Ranieri R, et al. White blood cells in obesity and diabetes: effects of weight loss and normalization of glucose metabolism. Diabetes Care. 2004;27:2501-2502.
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