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1.  Impact of visceral fat on gene expression profile in peripheral blood cells in obese Japanese subjects 
Visceral fat plays a central role in the development of metabolic syndrome and atherosclerotic cardiovascular diseases. The association of visceral fat accumulation with cardio-metabolic diseases has been reported, but the impact of visceral fat on the gene expression profile in peripheral blood cells remains to be determined. The aim of this study was to determine the effects of visceral fat area (VFA) and subcutaneous fat area (SFA) on the gene expression profile in peripheral blood cells of obese subjects.
All 17 enrolled subjects were hospitalized to receive diet therapy for obesity (defined as body mass index, BMI, greater than 25 kg/m2). VFA and SFA were measured at the umbilical level by computed tomography (CT). Blood samples were subjected to gene expression profile analysis by using SurePrint G3 Human GE Microarray 8 × 60 k ver. 2.0. The correlation between various clinical parameters, including VFA and SFA, and peripheral blood gene expression levels was analyzed.
Among the 17 subjects, 12 had normal glucose tolerance or borderline diabetes, and 5 were diagnosed with type 2 diabetes without medications [glycated hemoglobin (HbA1c); 6.3 ± 1.3%]. The mean BMI, VFA, and SFA were 30.0 ± 5.5 kg/m2, 177 ± 67 and 245 ± 131 cm2, respectively. Interestingly, VFA altered the expression of 1354 genes, including up-regulation of 307 and down-regulation of 1047, under the statistical environment that the parametric false discovery rate (FDR) was less than 0.1. However, no significant effects were noted for SFA or BMI. Gene ontology analysis showed higher prevalence of VFA-associated genes than that of SFA-associated genes, among the genes associated with inflammation, oxidative stress, immune response, lipid metabolism, and glucose metabolism.
Accumulation of visceral fat, but not subcutaneous fat, has a significant impact on the gene expression profile in peripheral blood cells in obese Japanese subjects.
PMCID: PMC5129204  PMID: 27899146
Obesity; Visceral fat; Subcutaneous fat; Fat distribution; Gene expression; Microarray; Metabolic syndrome; Diabetes; Adiponectin; KLF
2.  Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation 
Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in a considerable number of Japanese non-obese subjects (BMI <25 kg/m2). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation.
The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 ± 11.5 years, mean ± SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm2 using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity.
The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation (−) group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than (−) patients.
Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.
PMCID: PMC4301666  PMID: 25592402
Type 2 diabetes; Visceral fat accumulation; Adiponectin; Systemic arteriosclerosis; Vascular ultrasonography; Eating behavior
3.  Long-term impact of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on body weight and glycemic control in Japanese type 2 diabetes: an observational study 
Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been shown to possess pleiotropic effects including body weight reduction. However, long-term effect of liraglutide on body weight and glycemic control has not been elucidated in Japanese type 2 diabetes (T2D) subjects. Present study investigates whether liraglutide treatment maintains the body weight-decreasing and glucose-lowering effects for 2 years in Japanese T2D subjects.
The enrolled subjects were 86 T2D patients [age; 59.8 ± 12.8 years, duration of diabetes; 15.8 ± 9.5 years, glycated hemoglobin (HbA1c); 8.5 ± 1.5%, body mass index (BMI); 27.3 ± 5.4 kg/m2 (15.8 - 46.5 kg/m2), mean ± SD]. Among 86 subjects, liraglutide was introduced in 25 inpatients and 61 outpatients, and 46 subjects were followed for 2 years. Clinical parameters were measured at baseline and 3, 6, 9, 12, and 24 months after liraglutide introduction. The increase in liraglutide dosage and the additional usage of glucose-lowering agents depended on each attending physician.
At 1 year after liraglutide introduction, 69 patients (80.2%) decreased body weight and 58 patients (67.4%) improved glycemic control. Body mass index (BMI) was changed 27.3 ± 5.4 kg/m2 to 25.9 ± 4.8 kg/m2 and percent reduction of body weight was significant and maintained over 4% at 2 years after liraglutide introduction. HbA1c was significantly decreased from 8.5 ± 1.5% to 7.7 ± 1.2% for 2 years. Liraglutide treatment tended to ameliorate lipid profile and hepatic enzymes. Stepwise regression analysis demonstrated that baseline BMI and previous insulin dose were positively associated with body weight reduction and baseline HbA1c was positively associated with reduction of HbA1c at 2 years after liraglutide introduction.
Long-term liraglutide treatment effectively maintained the reduction of body weight and the fair glycemic control, and also improved lipid profile and liver enzymes in Japanese T2D subjects.
PMCID: PMC4167135  PMID: 25237400
Liraglutide; Glucagon-like peptide-1; Obesity; Diabetes; Metabolic syndrome; Eating behavior
4.  Ultrastructural Localization of Adiponectin protein in Vasculature of Normal and Atherosclerotic mice 
Scientific Reports  2014;4:4895.
Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild-type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis.
PMCID: PMC4013939  PMID: 24809933
5.  Efficacy of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on body weight, eating behavior, and glycemic control, in Japanese obese type 2 diabetes 
We recently reported that short-term treatment with liraglutide (20.0 ± 6.4 days) reduced body weight and improved some scales of eating behavior in Japanese type 2 diabetes inpatients. However, it remained uncertain whether such liraglutide-induced improvement is maintained after discharge from the hospital. The aim of the present study was to determine the long-term effects of liraglutide on body weight, glycemic control, and eating behavior in Japanese obese type 2 diabetics.
Patients with obesity (body mass index (BMI) >25 kg/m2) and type 2 diabetes were hospitalized at Osaka University Hospital between November 2010 and December 2011. BMI and glycated hemoglobin (HbA1c) were examined on admission, at discharge and at 1, 3, and 6 months after discharge. For the liraglutide group (BMI; 31.3 ± 5.3 kg/m2, n = 29), patients were introduced to liraglutide after correction of hyperglycemic by insulin or oral glucose-lowering drugs and maintained on liraglutide after discharge. Eating behavior was assessed in patients treated with liraglutide using The Guideline For Obesity questionnaire issued by the Japan Society for the Study of Obesity, at admission, discharge, 3 and 6 months after discharge. For the insulin group (BMI; 29.1 ± 3.0 kg/m2, n = 28), each patient was treated with insulin during hospitalization and glycemic control maintained by insulin after discharge.
Liraglutide induced significant and persistent weight loss from admission up to 6 months after discharge, while no change in body weight after discharge was noted in the insulin group. Liraglutide produced significant improvements in all major scores of eating behavior questionnaire items and such effect was maintained at 6 months after discharge. Weight loss correlated significantly with the decrease in scores for recognition of weight and constitution, sense of hunger, and eating style.
Liraglutide produced meaningful long-term weight loss and significantly improved eating behavior in obese Japanese patients with type 2 diabetes.
PMCID: PMC3459720  PMID: 22973968
Liraglutide; Glucagon-like peptide-1 (GLP-1); Obesity; Eating behavior; Diabetes; Incretin
6.  Short-term effects of liraglutide on visceral fat adiposity, appetite, and food preference: a pilot study of obese Japanese patients with type 2 diabetes 
To examine the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on visceral fat adiposity, appetite, food preference, and biomarkers of cardiovascular system in Japanese patients with type 2 diabetes.
The study subjects were 20 inpatients with type 2 diabetes treated with liraglutide [age; 61.2 ± 14.0 years, duration of diabetes; 16.9 ± 6.6 years, glycated hemoglobin (HbA1c); 9.1 ± 1.2%, body mass index (BMI); 28.3 ± 5.2 kg/m2, mean ± SD]. After improvement in glycemic control by insulin or oral glucose-lowering agents, patients were switched to liraglutide. We assessed the estimated visceral fat area (eVFA) by abdominal bioelectrical impedance analysis, glycemic control by the 75-g oral glucose tolerance test (OGTT) and eating behavior by the Japan Society for the Study of Obesity questionnaire.
Treatment with liraglutide (dose range: 0.3 to 0.9 mg/day) for 20.0 ± 6.4 days significantly reduced waist circumference, waist/hip ratio, eVFA. It also significantly improved the scores of eating behavior, food preference and the urge for fat intake and tended to reduce scores for sense of hunger. Liraglutide increased serum C-peptide immunoreactivity and disposition index.
Short-term treatment with liraglutide improved visceral fat adiposity, appetite, food preference and the urge for fat intake in obese Japanese patients with type 2 diabetes.
PMCID: PMC3260096  PMID: 22132774
liraglutide; glucagon-like peptide-1; obesity; eating behavior

Results 1-6 (6)