In adipocytes, hydrolysis of triglycerides results in the release of free fatty acids and glycerol. Aquaporin 7 (AQP7), a member of aquaglyceroporins, is known to permeabilize glycerol and water. We recently generated Aqp7-knockout (KO) mice and demonstrated that such mice have low plasma glycerol levels and impaired glycerol release in response to ␤3-adrenergic agonist, suggesting that AQP7 acts as a glycerol gateway molecule in adipocytes for the efficient release of glycerol in vivo. Although there was no difference in body weight between WT and KO mice until 10 weeks of age, here we found that KO mice developed adult-onset obesity. The body weight and fat mass increased significantly in KO mice compared with WT mice after 12 weeks of age. Adipocytes of KO mice were large and exhibited accumulation of triglycerides compared with WT mice. The KO mice developed obesity and insulin resistance even at a young age after consumption of high-fat͞high-sucrose diet. We demonstrated the enhanced glycerol kinase enzymatic activity in Aqp7-KO and -knockdown adipocytes. A series of our results indicate that AQP7 disruption elevates adipose glycerol kinase activity, accelerates triglycerides synthesis in adipocytes, and, finally, develops obesity.adipocyte ͉ insulin resistance ͉ triglyceride ͉ fatty acid

MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.

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. Adenovirusdelivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free 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 I 2 synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I 2 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.

Adipocytes hydrolyze triglycerides and secrete free fatty acids and glycerol into the circulation. The molecular mechanism involved in glycerol transport from adipocytes has not been elucidated. Here, we investigated glycerol and glucose metabolism in mice lacking aquaporin 7 (Aqp7), a member of the aquaglyceroporins expressed in adipose tissue, and demonstrated that Aqp7 functions as a glycerol gateway molecule in vivo. Aqp7-knockout (KO) mice had lower plasma glycerol levels compared with WT mice but had normal plasma free fatty acid levels. The increase in plasma glycerol level in response to ␤3-adrenergic agonist was severely impaired in KO mice. Epinephrine-stimulated glycerol secretion was also impaired in Aqp7 knockdown adipocytes. During prolonged fasting, plasma glycerol was elevated and the plasma glucose level was maintained in WT mice. In contrast, KO mice showed a disrupted increase of plasma glycerol and rapid reduction of plasma glucose during prolonged fasting. Our findings indicate that the lack of effective glycerol transport from adipocytes by glycerol gateway molecule causes defective adaptation to prolonged fasting.adipocyte ͉ gluconeogenesis ͉ lipolysis ͉ knockout mice

Objectives— Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II). Methods and Results— Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-α knockout (PPAR-α-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II–infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-α-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal–regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-α activity, whereas the adiponectin-dependent PPAR-α activation was diminished by Compound C, an inhibitor of AMPK. Conclusion— The present study suggests that adiponectin protects against Ang II–induced cardiac fibrosis possibly through AMPK-dependent PPAR-α activation.

Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease (CKD) associated with metabolic syndrome. The aim of this study was to determine the effects of treatment with angiotensin II (Ang II) type-1 receptor blocker (ARB) on the regulation of adipocytokines. Olmesartan, an ARB, significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice, without affecting body weight, but had no effect on plasma adiponectin levels in lean mice. Olmesartan also ameliorated dysregulation of adipocytokines in obesity, such as tumor necrosis factor-alpha, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, and serum amyloid A3. Olmesartan significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue. In cultured adipocytes, olmesartan acted as an antioxidant and improved adipocytokine dysregulation. Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated, at least in part, by targeting oxidative stress in obese adipose tissue. Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD.

Objective-Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule.We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPAR␣ ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. Methods and Results-Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPAR␣-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPAR␣ was knocked down by PPAR␣-RNAi. Conclusions-Our results suggest that fibrates enhance adiponectin partly through adipose PPAR␣ and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes. Key Words: adipocyte Ⅲ adiponectin Ⅲ fibrate Ⅲ metabolic syndrome Ⅲ peroxisome proliferator-activated receptor F ibrates have been used in clinical practice for Ͼ4 decades as a class of agents known to decrease triglyceride levels. Fibrates are also known to be peroxisome proliferator-activated receptor (PPAR)␣ ligands. Several clinical studies of fibrates have been performed in large populations. The Bezafibrate Infarction Prevention study (BIP) suggested that bezafibrate prevented cardiovascular events in the subgroup of coronary artery disease patients with high triglycerides. 1 Moreover, further subanalyses demonstrated that the administrations of bezafibrate significantly reduced new-onset diabetes 2,3 and myocardial infarction in the patients with the metabolic syndrome (MS). 4 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed that fenofibrate significantly reduced nonfatal myocardial infarctions and coronary revascularizations, a secondary endpoint, among patients with type 2 diabetes. 5 These favorable clinical outcomes in fibrate studies might be explained by not only its triglyceride-lowering effect but also its various PPAR␣-mediated pleiotropic effects.Adiponectin is an adipose-specific secretory protein and acts as an anti-diabetic and anti-atherosclerotic molecule. 6 Furthermore, a number of clinical trials showed that subjects with high levels of circulating adiponectin tend to be protected against type 2 diabetes and myocardial infarction. 7,8 Thiazolidi...

The present study was designed to evaluate the metabolism of chylomicron and chylomicron remnants by measuring serum apolipoprotein B-48 (apoB-48) levels in 335 normolipidemic and 253 hyperlipidemic subjects using a novel ELISA system. The distribution of fasting serum apoB-48 levels in normolipidemic subjects varied widely, ranging from Ͻ 1 to Ͼ 24 g/ml (mean, 5.2 ؎ 3.8 g/ml; median, 3.9 g/ml). Serum apoB-48 levels correlated with serum triglyceride (TG) concentrations ( r ‫؍‬ 0.45, P Ͻ 0.001), but not with total cholesterol levels. Serum apoB-48 levels were 7 to 18 times higher in patients with Type I, Type V, and Type III hyperlipidemia, and only slightly higher in patients with Type IIa, Type IIb, and Type IV hyperlipidemia, compared with normolipidemic subjects. The calculated apoB-48/ TG ratio was elevated only in patients with dysbetalipoproteinemia (apoE2/2 phenotype). In normolipidemic subjects, oral fat loading resulted in about 2-fold increase in serum apoB-48 levels, with a peak level recorded at 3-4 h postloading, and then returned to the baseline level within 6 h. On the other hand, in patients with dysbetalipoproteinemia, serum apoB-48 levels did not change considerably. Our results indicate that serum apoB-48 is a very useful parameter for evaluating lipoprotein metabolism in exogenous pathways. The pathogenic role of hypertriglyceridemia in atherosclerosis has long been elusive. A recent meta analysis of several cohort studies revealed that plasma triglyceride (TG) level is an independent risk factor for cardiovascular diseases (1). The relationship between plasma TG levels and atherosclerotic diseases has often been discussed in relation to postprandial hyperlipidemia (2-7). Several studies have pointed to the relationship between the impaired metabolism of postprandial TG-rich lipoproteins (TRLs) and the presence or development of coronary heart disease (CHD). A mechanistic hypothesis linking the postprandial generation of TRL remnants (products of lipolytic degradation of TRL produced by the liver, VLDL, and by the intestine chylomicrons) to the development of atherosclerosis was formulated almost 20 years ago by Zilversmit (8). TG-depleted remnants are considered to be atherogenic because they can penetrate the mucosal lining of the arterial wall and become entrapped within the subendothelial space. Thus, accurate evaluation of the kinetics of chylomicron and chylomicron remnants is very important.Chylomicrons are secreted by the intestine after fat ingestion. Chylomicron particles contain apolipoprotein B-48 (apoB-48) as the structural protein, which in humans is formed exclusively in the intestine after tissue-specific editing of the apoB-100 mRNA (9, 10). Different methods are used for estimation of postprandial lipoproteins. A number of studies have made use of retinyl palmitate (RP) labeling of chylomicrons, together with postprandial plasma TG quantification. The RP technique has shortcomings as it has recently been shown that RP can exchange between lipoprotein species in pla...