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

Abstract

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-␥ 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 dietinduced 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-␣, interferon-␥, 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. Key Words: valsartan Ⅲ angiotensin type 1 receptor Ⅲ inflammation Ⅲ adipose tissue Ⅲ macrophages Ⅲ islets O besity is a metabolic disorder characterized by chronic inflammation and dyslipidemia and is a strong predictor for the development of hypertension, diabetes mellitus, and cardiovascular disease. One potential pharmacological target for treating obesity-related metabolic disorders is angiotensin II, a regulator of cardiovascular homeostasis (reviewed in Reference 1). Dysregulated angiotensin activity leads to hypertension and other cardiovascular complications. Specific inhibitors, such as the angiotensin type 1 receptor (AT1R) blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, have implicated this pathway also in the development of metabolic diseases, like obesity and type 2 diabetes mellitus. A meta-analysis of clinical trials with these inhibitors revealed an overall 25% reduction in new-onset diabetes mellitus. 2 In addition, ARB treatment decreases fat cell volume and fat accumulation and improves differentiation of adipocytes, which is associated with a more insulin-sensitive phenotype. [3][4][5][6] Thu...

Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

“…Also, laser-captured ␤-cells from patients with type 2 diabetes compared with nondiabetic controls have elevated levels of various cytokines and chemokines (38). Previous findings from our group, as well as results from this study, showed increased production of inflammatory cytokines in the islets of C57Bl/6 mice on high-fat diets (13,43). Our present results are the first ones to Fig.…”

“…Samples of epididymal adipose tissue (0.1-0.3 g) were digested with collagenase as described before, with minor modifications (13,53). Briefly, finely minced adipose tissue was incubated for 1 h at 37°C in a shaking water bath in KRH buffer supplemented with 1% BSA, 20 nmol/l adenosine, and 1 mg/ml collagenase I.…”

Angiotensin II Induces Interleukin-1β–Mediated Islet Inflammation and β-Cell Dysfunction Independently of Vasoconstrictive Effects

“…Furthermore, in clinical trials treatment with angiotensin II receptor antagonists reduced the proinflammatory markers TNF-a, IL-6, and CRP (40,41), as well as MCP-1, in the circulation of patients with cardiovascular diseases (42). Similarly, in HFD-fed mice, decreased serum concentrations of interferon-g and MCP-1 and diminished proinflammatory gene expression in pancreatic islets were observed with angiotensin II receptor antagonists or ACE inhibitors (24,43).…”

“…In skeletal muscle angiotensin II interferes with glucose uptake by decreasing GLUT4 translocation to the plasma membrane (22) and induces insulin resistance (23). RAS inhibition prevents these effects in vivo, resulting in increased glucose tolerance and improved islet function (2,8,9,24). However, whether the amelioration of metabolic parameters is a consequence of normalization of vasoconstriction or due to inhibition of local RAS is unclear.…”

Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

“…202 Moreover, multiple investigations have observed significant reductions in adipose tissue gene expression of proinflammatory cytokines and macrophages as well as elevations in adiponectin levels after ARB administration in obese rodents. 101,170,201 These inflammatory alterations were associated with an improvement in whole-body insulin sensitivity. 203 Overall, RAS activity may play a key role in adipose tissue inflammation and insulin resistance in obesity.…”