メタボ対策に応用できるアディポネクチン測定

A rapid increase in the number of people who develop metabolic syndrome（MetS）is drawing much attention, since MetS-associated complications, such as cardiovascular diseases, are not only life-threatening, but also remarkably impair the quality of life for those who have MetS. Thus, developing a method to identify those who are at risk of developing MetS is crucial to maintain their quality of life and reduce the burden on society to provide care, since such a method will enable early intervention for those who may be at risk and prevent them from developing MetS. Here we report from two prospective cohort studies that the cut-off value of serum total adiponectin level for managing the risk of developing MetS is６．２μg／ml in male and６．５μg／ml in female. Subjects with total adiponectin level equal to or lower than the cut-off value developed MetS more rapidly than did those with total adiponectin level higher than the cut-off value. A follow up study validated the cutoff value of total adiponectin level in both male and female. Furthermore, evaluating the risk of developing MetS in future by adiponectin level successfully identified those who are at risk among people who are not obese by their anthropometric measurements. These results provide evidence that adiponectin level is able to serve as a biomarker for predicting future onset of MetS

Saturated fatty acids and insulin resistance

Insulin resistance is one of the pathophysiological features of obesity and type 2 diabetes. Recent findings have linked insulin resistance to chronic low-grade inflammation in white adipose tissue. Excess storage of saturated fat in white adipose tissue due to a modern life style causes hypertrophy and hyperplasia of adipocytes, which exhibit attenuated insulin signaling due to their production and release of saturated fatty acids. These adipocytes recruit macrophages to white adipose tissue and, together with them, initiate a proinflammatory response. Proinflammatory factors and saturated fatty acids secreted into the bloodstream from white adipose tissue impair insulin signaling in nonadipose tissues, which causes whole-body insulin resistance

Potential Role of Free Fatty Acids in the Pathogenesis of Periodontitis and Primary Sjögren's Syndrome

Clinical studies have shown that metabolic disorders such as type 2 diabetes and dyslipidemia are associated with increased risk of oral-related diseases, such as periodontitis and Sjögren’s syndrome. Although changes in the immune system are critical in both of these metabolic disorders and oral-related diseases, the mechanism underlying the interaction between these diseases remains largely unknown. Obesity and type 2 diabetes are known to be associated with higher concentrations of free fatty acids in blood. Among free fatty acids, saturated fatty acids such as palmitic acid have been demonstrated to induce inflammatory responses mainly via the innate immune systems, and to be involved in the pathogenesis of type 2 diabetes in tissues such as adipose tissue, liver, pancreas, and skeletal muscle. Here, we highlight recent advances in evidence for the potential involvement of palmitic acid in the pathogenesis of periodontitis and Sjögren’s syndrome, and discuss the possibility that improvement of the lipid profile could be a new strategy for the treatment of these diseases

Extracellular matrix with the rigidity of adipose tissue helps 3T3-L1 adipocytes maintain insulin responsiveness

Despite the popularity of 3T3-L1 adipocytes as a model system of adipocytes in vivo, they do not carry all of the cellular functions of adipocytes in vivo. In this study, we investigated the effect of extracellular matrix (ECM) rigidity on insulin signal transduction in 3T3-L1 adipocytes. On 250 Pa polyacrylamide gel (soft gel) laminated with a mixture of collagen type 1 and fibronectin, whose rigidity matches that of adipose tissue, expression of the insulin receptor, IRS-1 and AKT was upregulated and their insulin-stimulated phosphorylation was enhanced. Furthermore, the expression of GLUT1 was downregulated, whereas the expression of GLUT4 was unaffected as ECM rigidity decreased. Insulin-stimulated GLUT4 recruitment to the plasma membrane was significantly enhanced in cells seeded on soft gel. These results suggest that adjusting the ECM rigidity to that of adipose tissue augments insulin signaling in 3T3-L1 adipocytes and enhances insulin-stimulated GLUT4 recruitment to the plasma membrane

Cut-Off Value of Total Adiponectin

Aim To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers. Methods A total of 365 subjects without MetS aged 20–60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS. Results During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (≤ 4.9, 5.0–6.6, 6.7–8.8 and ≥ 8.9 μg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02–0.78; P = 0.03) in subjects with total adiponectin level of 5.0–6.6 μg/ml, and 0.15 (95% CI 0.02–0.97; P = 0.047) in subjects with total adiponectin level ≤ 4.9 μg/ml compared with those with total adiponectin level ≥ 8.9 μg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 μg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level ≤ 6.2 μg/ml compared with > 6.2 μg/ml (TR 0.22, 95% CI: 0.08–0.64, P = 0.005). Conclusion Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 μg/ml in male Japanese workers. Subjects with total adiponectin level ≤ 6.2 μg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 μg/ml

Palmitoylation of the canine histamine H2 receptor occurs at Cys305 and is important for cell surface targeting

AbstractTo determine the presence and functional role of the histamine H2 receptor (H2R) palmitoylation, a receptor with a Cys305 to Ala (A305 receptor) mutation was generated. Wild-type (WT) and A305 receptors were tagged at their N-termini with a hemagglutinin (HA) epitope. WT, but not A305, receptors incorporated [3H]palmitate by metabolic labeling, indicating that the H2R is palmitoylated at Cys305. Immunocytochemistry of WT and A305 receptors expressed in COS7 cells revealed WT receptors to be distributed at the plasma membrane, while the majority of A305 receptors were localized intracellularly with only a small portion being at the plasma membrane. However, the affinity of the A305 receptor for tiotidine was comparable to that of the WT receptor. In addition, when the amounts of cell surface receptors as determined by anti-HA antibody binding were equivalent, A305 receptors mediated production of more cAMP than WT receptors. Preincubation of COS7 cells expressing each receptor with 10−5 M histamine for 30 min reduced subsequent cAMP production in response to histamine via the receptors to similar extents, indicating that palmitoylation is not necessary for desensitization. In addition, cell surface A305 receptors were capable of being internalized from the cell surface at a rate and extent similar to those of WT receptors. Finally, CHO cell lines stably expressing either WT or A305 receptors were incubated with 10−5 M histamine for 1, 6, 12 and 24 h. Total amounts of WT and A305 receptors, as determined by tiotidine binding, were reduced by incubation, indicating downregulation. Downregulation of the A305 receptor was more extensive than that of the WT receptor. Thus, palmitoylation of the H2R might be important for targeting to the cell surface and stability

Development of fully automated and ultrasensitive assays for urinary adiponectin and their application as novel biomarkers for diabetic kidney disease

Glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) are used to diagnose and classify the severity of chronic kidney disease. Total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) assays were developed using the fully automated immunoassay system, HI-1000 and their significance over conventional biomarkers were investigated. The T-AN and H-AN assays had high reproducibility, good linearity, and sufficient sensitivity to detect trace amounts of adiponectin in the urine. Urine samples after gel filtration were analyzed for the presence of different molecular isoforms. Low molecular weight (LMW) forms and monomers were the major components (93%) of adiponectin in the urine from a diabetic patient with normoalbuminuria. Urine from a microalbuminuria patient contained both high molecular weight (HMW) (11%) and middle molecular weight (MMW) (28%) adiponectin, although the LMW level was still high (52%). The amount of HMW (32%) and MMW (42%) were more abundant than that of LMW (24%) in a diabetic patient with macroalbuminuria. T-AN (r = − 0.43) and H-AN (r = − 0.38) levels showed higher correlation with estimated GFR (eGFR) than UAER (r = − 0.23). Urinary levels of both T-AN and H-AN negatively correlated with renal function in diabetic patients and they may serve as new biomarkers for diabetic kidney disease