Kana Inoue

Short-term effects of liraglutide on visceral fat adiposity, appetite, and food preference: a pilot study of obese Japanese patients with type 2 diabetes

BackgroundTo 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.MethodsThe 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.ResultsTreatment 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.ConclusionsShort-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.

Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin‐secreting capacity

Aims/Introduction:  Recently, glucagon‐like peptide‐1 (GLP‐1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide‐effective patients from liraglutide‐ineffective patients.

Positive Feedback Regulation Between Adiponectin and T-Cadherin Impacts Adiponectin Levels in Tissue and Plasma of Male Mice

Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.

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

BackgroundWe 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.MethodsPatients 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.ResultsLiraglutide 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.ConclusionLiraglutide produced meaningful long-term weight loss and significantly improved eating behavior in obese Japanese patients with type 2 diabetes.

Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome).

OBJECTIVE Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells. APPROACH AND RESULTS Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m2 according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4×44K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP. CONCLUSIONS Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation.

High prevalence of gastroesophageal reflux symptoms in type 2 diabetics with hypoadiponectinemia and metabolic syndrome

BackgroundThe prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide. Abdominal obesity or visceral fat accumulation rather than simple obesity is associated with GERD. Previous reports demonstrated the association between GERD and type 2 diabetes mellitus (T2DM). Signification of visceral fat accumulation and adiponectin in T2DM patients with GERD remains unclear. The present study investigated the relationships between GERD symptoms, visceral fat accumulation and adiponectin in subjects with T2DM.FindingsThe study (ADMIT study) subjects were 66 Japanese T2DM outpatients, who answered the questionnaire regarding GERD symptoms in Frequency Scale for the Symptoms of GERD (FSSG), and were measured visceral fat area by bioelectrical impedance analysis. Patients with FSSG scores of more than 8 were considered as positive. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with the metabolic syndrome (Mets) were significantly higher compared to those without Mets. The prevalence of FSSG score ≥ 8 and average FSSG score in T2DM subjects with low levels of serum adiponectin were significantly higher compared to those with high levels of serum adiponectin. Moreover, the combination of Mets and hypoadiponectinemia had a multiplicative effect on GERD symptom score (p = 0.047).ConclusionsOur study showed that the coexistence of MetS and low levels of serum adiponectin was associated with the higher prevalence of FSSG score ≥ 8 and the higher scores of GERD symptom in subjects with T2DM.Trial RegistrationUMIN 000002271.

Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation.

BackgroundVisceral 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.MethodsThe 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.ResultsThe 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.ConclusionsType 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.

A Novel Role for Adipose Ephrin-B1 in Inflammatory Response

Aims Ephrin-B1 (EfnB1) was selected among genes of unknown function in adipocytes or adipose tissue and subjected to thorough analysis to understand its role in the development of obesity. Methods and Results EfnB1 mRNA and protein levels were significantly decreased in adipose tissues of obese mice and such reduction was mainly observed in mature adipocytes. Exposure of 3T3-L1 adipocytes to tumor necrosis factor-α (TNF-α) and their culture with RAW264.7 cells reduced EFNB1 levels. Knockdown of adipose EFNB1 increased monocyte chemoattractant protein-1 (Mcp-1) mRNA level and augmented the TNF-α-mediated THP-1 monocyte adhesion to adipocytes. Adenovirus-mediated adipose EFNB1-overexpression significantly reduced the increase in Mcp-1 mRNA level induced by coculture of 3T3-L1 adipocytes with RAW264.7 cells. Monocyte adherent assay showed that adipose EfnB1-overexpression significantly decreased the increase of monocyte adhesion by coculture with RAW264.7 cells. TNF-α-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was reduced by EFNB1-overexpression. Conclusions EFNB1 contributes to the suppression of adipose inflammatory response. In obesity, reduction of adipose EFNB1 may accelerate the vicious cycle involved in adipose tissue inflammation.

Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat.

Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.

Possible involvement of Opa-interacting protein 5 in adipose proliferation and obesity.

Obesity is an epidemic matter increasing risk for cardiovascular diseases and metabolic disorders such as type 2 diabetes. We recently examined the association between visceral fat adiposity and gene expression profile of peripheral blood cells in human subjects. In a series of studies, Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) was nominated as a molecule of unknown function in adipocytes and thus the present study was performed to investigate the role of OIP5 in obesity. Adenovirus overexpressing Oip5 (Ad-Oip5) was generated and infected to 3T3-L1 cells stably expressing Coxsackie-Adenovirus Receptor (CAR-3T3-L1) and to mouse subcutaneous fat. For a knockdown experiment, siRNA against Oip5 (Oip5-siRNA) was introduced into 3T3-L1 cells. Proliferation of adipose cells was measured by BrdU uptake, EdU-staining, and cell count. Significant increase of Oip5 mRNA level was observed in obese white adipose tissues and such increase was detected in both mature adipocytes fraction and stromal vascular cell fraction. Ad-Oip5-infected CAR-3T3-L1 preadipocytes and adipocytes proliferated rapidly, while a significant reduction of proliferation was observed in Oip5-siRNA-introduced 3T3-L1 preadipocytes. Fat weight and number of adipocytes were significantly increased in Ad-Oip5-administered fat tissues. Oip5 promotes proliferation of pre- and mature-adipocytes and contributes adipose hyperplasia. Increase of Oip5 may associate with development of obesity.