The ratio of equol non-producers in overweight or obese populations might be higher than generally reported. Natural S-equol might have a role in glycaemic control and in the prevention of cardiovascular disease by its effects to lower LDL-C levels and CAVI scores in overweight or obese individuals.

Effect of pioglitazone T he monocyte-macrophage system exists in at least two distinct phenotypes of differentiation: proinflammatory (M1) and anti-inflammatory (M2) (1,2). Macrophages, when infiltrated into obese adipose tissue, exhibit a phenotypic switch from M2 to M1 polarization, thereby contributing to obesity-induced adipose tissue inflammation and insulin resistance (1). Expression of both M1 and M2 markers is detected in circulating peripheral blood mononuclear cells as well as in atherosclerotic plaques (3). However, there have been no detailed studies on the M1/M2 phenotype of monocytes and their association with cardiovascular risks in obese subjects with type 2 diabetes. On the other hand, we demonstrated that pioglitazone, a thiazolidinedione class of insulin sensitizer, exerts an antiatherogenic effect independent of its antidiabetic effect (4). Here, we investigated the M1/M2 phenotype of peripheral blood monocytes and pulse wave velocity (PWV), an established index of arterial stiffness, and also the effect of pioglitazone in obese diabetic patients.A total of 161 subjects (95 men and 66 women, mean age 50.4 years), including 45 normal-weight control subjects, 62 obese nondiabetic patients, and 54 obese diabetic patients with or without pioglitazone treatment for 3 months (30 mg daily), were recruited in our clinic. Peripheral blood monocytes were prepared using magnetic-assisted cell sorting and flow cytometry with anti-CD14. Expression of M1/M2 markers was analyzed by real-time quantitative PCR method and flow cytometry. The number and percentage of CD14 ϩ cells among peripheral blood monocytes from obese diabetic patients were significantly increased relative to those of control subjects (P Ͻ 0.05).The CD14 ϩ cells from obese nondiabetic patients showed significantly higher expression of M1 markers, tumor necrosis factor-␣, and interleukin (IL)-6 and lower expression of an M2 marker, IL-10, relative to control subjects (P Ͻ 0.01). This is consistent with a report that peripheral blood mononuclear cells in obesity are in an inflammatory state (5). In addition, expression of IL-10 and CD163 in CD14 ϩ cells from obese diabetic patients was significantly decreased relative to that of obese nondiabetic patients (P Ͻ 0.01). Multivariate regression analysis showed that expression of tumor necrosis factor-␣ is independently associated with age and BMI and that expression of IL-6 is independently associated with BMI and LDL cholesterol (P Ͻ 0.01); expression of IL-10 was negatively and independently associated with diastolic blood pressure, A1C, and triglycerides, and expression of CD163 was negatively and independently associated with insulin concentration, A1C, and PWV (P Ͻ 0.05). Moreover, only age and CD163 were independently correlated with PWV (P Ͻ 0.05). Interestingly, 3-month treatment with pioglitazone significantly increased IL-10 and CD163 and decreased IL-6 (P Ͻ 0.05) in parallel with the improvement of fasting plasma glucose, A1C, insulin conc e n t r a t i o n , h o m e o s t a s i s m o ...

A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, reduces the incidence of cardiovascular diseases. However, the detailed mechanism underlying the anti-atherogenic effect of EPA is still poorly understood. In this study, we examined the effect of EPA on cardio-ankle vascular index (CAVI), a new index of arterial stiffness that is less influenced by blood pressure (BP), as well as on serum amyloid A-low-density lipoprotein (SAA-LDL), an oxidized LDL (oxLDL), in the metabolic syndrome. Ninety-two obese Japanese subjects with metabolic syndromes were randomly divided into two groups (n¼46): the EPA-treated group (1.8 g administered daily for 3 months) and the control group. Measurements were taken to assess the changes in glucose-lipid metabolism, SAA-LDL, C-reactive protein (CRP), leptin, adiponectin and pulse wave velocity (PWV), and CAVI. EPA treatment significantly reduced the levels of immunoreactive insulin, triglycerides, SAA-LDL, CRP, PWV and CAVI and increased the levels of adiponectin relative to the control group for 3 months (Po0.05). Stepwise multivariate linear regression analysis revealed that the only significant determinant for a decrease in CAVI by EPA is a reduction in SAA-LDL (Po0.05). Moreover, the EPA-induced reduction of SAA-LDL was only significantly correlated with a decrease in total cholesterol and an increase in adiponectin (Po0.05). This study is the first demonstration that EPA improves arterial stiffness and is less influenced by BP, possibly through the suppression of SAA-LDL, thereby leading to a reduction in the frequency of cardiovascular disease development in metabolic syndrome.

SummaryBackground and Objectives Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. Design, setting, participants, & measurementsThe U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study.Results UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P Ͻ 0.05). Interestingly, diet-and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P Ͻ 0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. ConclusionsThis study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that UCysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

OBJECTIVEIt has recently been highlighted that proinflammatory (M1) macrophages predominate over anti-inflammatory (M2) macrophages in obesity, thereby contributing to obesity-induced adipose inflammation and insulin resistance. A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA) reduces the incidence of major coronary events. In this study, we examined the effect of EPA on M1/M2-like phenotypes of peripheral blood monocytes in obese dyslipidemic patients.RESEARCH DESIGN AND METHODSPeripheral blood monocytes were prepared from 26 obese patients without and 90 obese patients with dyslipidemia. Of the latter 90 obese patients with dyslipidemia, 82 patients were treated with or without EPA treatment (1.8 g daily) for 3 months.RESULTSMonocytes in obese patients with dyslipidemia showed a significantly lower expression of interleukin-10 (IL-10), an M2 marker, than those without dyslipidemia. EPA significantly increased serum IL-10 and EPA levels, the EPA/arachidonic acid (AA) ratio, and monocyte IL-10 expression and decreased the pulse wave velocity (PWV), an index of arterial stiffness, compared with the control group. After EPA treatment, the serum EPA/AA ratio was significantly correlated with monocyte IL-10 expression. Only increases in monocyte IL-10 expression and serum adiponectin were independent determinants of a decreased PWV by EPA. Furthermore, EPA significantly increased the expression and secretion of IL-10 in human monocytic THP-1 cells through a peroxisome proliferator–activated receptor (PPAR)γ-dependent pathway.CONCLUSIONSThis study is the first to show that EPA increases the monocyte IL-10 expression in parallel with decrease of arterial stiffness, which may contribute to the antiatherogenic effect of EPA in obese dyslipidemic patients.