Valsartan Protects Pancreatic Islets and Adipose Tissue From the Inflammatory and Metabolic Consequences of a High-Fat Diet in Mice

Abstract

Obesity, hypertension, cardiovascular disease, and inflammation are closely associated with the rising incidence of diabetes mellitus. One pharmacological target that may have significant potential to lower the risk of obesity-related diseases is the angiotensin type 1 receptor (AT1R). We examined the hypothesis that the AT1R blocker valsartan reduces the metabolic consequences and inflammatory effects of a high-fat (Western) diet in mice. C57BL/6J mice were treated by oral gavage with 10 mg/kg per day of valsartan or vehicle and placed on either a standard chow or Western diet for 12 weeks. Western diet-fed mice given valsartan had improved glucose tolerance, reduced fasting blood glucose levels, and reduced serum insulin levels compared with mice fed a Western diet alone. Valsartan treatment also blocked Western diet–induced increases in serum levels of the proinflammatory cytokines interferon-γ and monocyte chemotactic protein 1. In the pancreatic islets, valsartan enhanced mitochondrial function and prevented Western diet–induced decreases in glucose-stimulated insulin secretion. In adipose tissue, valsartan reduced Western diet–induced macrophage infiltration and expression of macrophage-derived monocyte chemotactic protein 1. In isolated adipocytes, valsartan treatment blocked or attenuated Western diet–induced changes in expression of several key inflammatory signals: interleukin 12p40, interleukin 12p35, tumor necrosis factor-α, interferon-γ, adiponectin, platelet 12-lipoxygenase, collagen 6, inducible NO synthase, and AT1R. Our findings indicate that AT1R blockade with valsartan attenuated several deleterious effects of the Western diet at the systemic and local levels in islets and adipose tissue. This study suggests that AT1R blockers provide additional therapeutic benefits in the metabolic syndrome and other obesity-related disorders beyond lowering blood pressure.