Adiponectin Replenishment Ameliorates Obesity-Related Hypertension
作者：Koji Ohashi; Shinji Kihara; Noriyuki Ouchi; Masahiro Kumada; Koichi Fujita; Aki Hiuge; Toshiyuki Hibuse; Miwa Ryo; Hitoshi Nishizawa; Norikazu Maeda; Kazuhisa Maeda; Rei Shibata; Kenneth Walsh; Tohru Funahashi; Iichiro Shimomura
【關鍵詞】 Ameliorates
the Department of Metabolic Medicine (K.O., S.K.,
M.K., K.F., A.H., T.H., M.R., H.N., N.M., K.M., T.F., I.S.), Graduate
School of Medicine, Osaka University, Osaka, Japan
Molecular Cardiology/Whitaker Cardiovascular Institute (N.O., R.S.,
K.W.), Boston University School of Medicine, Boston, Mass.
Abstract
Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-delivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistancefree state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I2 synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I2 synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.
Key Words: hypertension, obesity nitric oxide synthase sodium, dietary L-NAME
Introduction
The cluster of hypertension, diabetes mellitus, and dyslipidemia in upper body obesity, collectively referred to as the metabolic syndrome, is a common cause of atherosclerotic cardiovascular diseases and one of the most serious threats to public health. Adipose tissue produces and secretes many bioactive substances,14 conceptualized as adipocytokines.3 Dysregulated production of adipocytokines, such as tumor necrosis factor-, leptin, and plasminogen activator inhibitor type 1, is associated with the pathophysiology of obesity-related disorders.13
Adiponectin is an antiatherogenic48 and antidiabetic913 adipocytokine, identified by our group through the screening of adipose-specific genes in the human cDNA project.14 Other groups independently cloned the mouse homologue of adiponectin as ACRP30 and AdipoQ, respectively.15,16 Adiponectin is a plasma protein exclusively produced by adipose tissue,14 and the plasma concentrations decreased in patients with obesity,17 coronary artery disease,18 type 2 diabetes,19 and hypertension.20 The adiponectin gene is located on chromosome 3q27, which was reported to replicate linkage with the metabolic syndrome.21 Recently, we demonstrated that the I164T mutation of the adiponectin gene affects the prevalence of coronary artery disease and obesity-unrelated clustering of hypertension, diabetes mellitus, and dyslipidemia.22
Human studies of the vasodilator response to reactive hyperemia revealed that plasma adiponectin levels correlated significantly with endothelium-dependent vasodilation.23 Moreover, adiponectin treatment suppressed apoptosis by activating AMP-activated protein kinase, Akt kinase, and endothelial NO synthase (eNOS) signaling axis in cultured human endothelial cells.24,25 These data suggest that adiponectin is a protective factor against endothelial injury and that low production of adiponectin might relate to the pathophysiology of hypertension.
We reported previously that the adiponectin-knockout (KO) mice exhibited obesity, insulin resistance, and hypertension when fed a high-fat/high-sucrose/high-salt diet for 4 weeks.23 In clinical studies, obesity, hypoadiponectinemia, insulin resistance, and hypertension are closely associated with one another in the metabolic syndrome.11,19,20,2628 Based on this background, it is important to define the direct relationship between hypoadiponectinemia and hypertension. The results of the present study showed that KKAy mice exhibited hypoadiponectinemia. KKAy mice develop maturity-onset obesity through the antagonism of the hypothalamic melanocortin system by ectopic expression of the agouti protein. The agouti and agouti-related protein compete with proopiomelanocortin-derived peptides for binding sites on melanocortin receptors to regulate food intake and energy expenditure. Furthermore, numerous studies have demonstrated that KKAy mice are good models of the metabolic syndrome, such as hypertension and diabetes mellitus.29,30 In the present study, we showed for the first time that adiponectin replenishment improved the hypertension of KKAy mice. In addition, we induced hypertension in adiponectin KO mice by providing a high-salt diet without affecting insulin resistance. Therefore, we advance the concept that obesity-related hypoadiponectinemia contributes to the development of hypertension both directly and indirectly via insulin resistance. Our results also suggest that adiponectin therapy is potentially useful for patients with the metabolic syndrome, especially those with hypertension and insulin resistance.