Guided Internet-Based Cognitive Behavioral Therapy in Japanese Patients With Obsessive-Compulsive Disorder: Protocol for a Randomized Controlled Trial.

BACKGROUND: Cognitive behavioral therapy for obsessive-compulsive disorder has been established, but access to this therapy in Japan is limited. Internet-based cognitive behavioral therapy may improve treatment accessibility and sufficiently improve obsessive-compulsive symptoms. There are few randomized controlled trials examining the effectiveness of internet-based cognitive behavioral therapy in patients with obsessive-compulsive disorder. We designed a randomized controlled trial protocol to assess the effectiveness of guided internet-based cognitive behavioral therapy in Japanese patients with obsessive-compulsive disorder. OBJECTIVE: We aimed to develop a protocol for a randomized controlled trial of internet-based cognitive behavioral therapy in Japanese patients with obsessive-compulsive disorder. METHODS: The randomized controlled trial will compare internet-based cognitive behavioral therapy treatment and usual care groups, each consisting of 15 participants (n=30) diagnosed with obsessive-compulsive disorder. We will evaluate the effectiveness of a 12-week intervention. The primary outcome of symptom severity will be measured using the Yale-Brown Obsessive-Compulsive Scale. Secondary outcomes will be assessed with the Obsessive-Compulsive Inventory, Beck Anxiety Inventory, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Working Alliance Inventory-Short Form, and the Euro Qol - 5 Dimension. All measures will be assessed at weeks 0 (baseline) and 12 (follow-up). In the statistical analysis comparing treatment effects, the least-squares means and their 95% CIs will be estimated by analysis of covariance with the change in total outcomes scores at week 12. All comparisons are planned, and all P values will be two-sided, with values <.05 considered statistically significant. RESULTS: The study will be performed from January 2020 to March 2021, and results are expected to be available in mid-2021. CONCLUSIONS: The trial will demonstrate whether internet-based cognitive behavioral therapy improves access and is more effective than more usual care for patients with obsessive-compulsive disorder in Japan. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) 000039375; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000044422. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18216.

The Development of a Novel, Validated, Rapid and Simple Method for the Detection of Sarcocystis fayeri in Horse Meat in the Sanitary Control Setting.

Sarcocystis fayeri (S. fayeri) is a newly identified causative agent of foodborne disease that is associated with the consumption of raw horse meat. The testing methods prescribed by the Ministry of Health, Labour and Welfare of Japan are time consuming and require the use of expensive equipment and a high level of technical expertise. Accordingly, these methods are not suitable for use in the routine sanitary control setting to prevent outbreaks of foodborne disease. In order to solve these problems, we have developed a new, rapid and simple testing method using LAMP, which takes only 1 hour to perform and which does not involve the use of any expensive equipment or expert techniques. For the validation of this method, an inter-laboratory study was performed among 5 institutes using 10 samples infected with various concentrations of S. fayeri. The results of the inter-laboratory study demonstrated that our LAMP method could detect S. fayeri at concentrations greater than 10(4) copies/g. Thus, this new method could be useful in screening for S. fayeri as a routine sanitary control procedure.

An Efficient Purification Method for Quantitative Determinations of Protodioscin, Dioscin and Diosgenin in Plasma of Fenugreek-Fed Mice.

An efficient purification method for simultaneous recovery of polar saponins, protodioscin (PD) and dioscin (DC), and non-polar aglycon, diosgenin (DG), from plasma of mice fed diets containing seed flours of fenugreek (Trigonella foenum-graecum) was established for subsequent quantitative analysis by LC-ESI-MS/MS. Mice plasma samples were first deproteinated by addition of acetonitrile, and the supernatant was applied to a carbon-based solid phase extraction tube. After successive washing with methanol and 35% chroloform/methanol (v/v), PD, DC and DG were eluted simultaneously with 80% chroloform/methanol (v/v). The eluate was evaporated to dryness, and re-dissolved in 80% methanol (v/v). The filtered sample was analyzed with an LC-ESI-MS/MS system. After the purification procedure, recovery rates between 89.3 to 117.4% were obtained without notable ion suppression or enhancement. The use of internal standards was therefore not necessary. The utility of the method was demonstrated by analyzing plasma of mice from a fenugreek feeding study.

Yamogenin in fenugreek inhibits lipid accumulation through the suppression of gene expression in fatty acid synthesis in hepatocytes.

Yamogenin is a diastereomer of diosgenin, which we have identified as the compound responsible for the anti-hyperlipidemic effect of fenugreek. Here, we examined the effects of yamogenin on the accumulation of triacylglyceride (TG) in hepatocytes, because yamogenin is also contained in fenugreek. It was demonstrated that yamogenin also inhibited TG accumulation in HepG2 hepatocytes and suppressed the mRNA expression of fatty acid synthesis-related genes such as fatty acid synthase and sterol response element-binding protein-1c. Indeed, yamogenin also antagonized the activation of the liver X receptor (LXR) in luciferase ligand assay similar to diosgenin. However, yamogenin could not exert such effects in the presence of T0901713, a potent agonist of LXR. These findings indicate that the effects of yamogenin on TG accumulation would be weaker than those of diosgenin, suggesting that the structural difference between yamogenin and diosgenin would be important for the inhibition of LXR activation.

Bixin activates PPARα and improves obesity-induced abnormalities of carbohydrate and lipid metabolism in mice.

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates the expression of the genes involved in fatty acid oxidation. PPARα activators induce fatty acid oxidation in the liver, thereby improving lipid and carbohydrate metabolism in obese mice. In this study, the dietary cis-carotenoids bixin and norbixin, which are commonly used in the food coloring industry, were found to activate PPARα by luciferase reporter assays using GAL4/PPARα chimeric and full-length PPARα systems. Treatment with bixin and norbixin induced the mRNA expression of PPARα target genes involved in fatty acid oxidation in PPARα-expressing HepG2 hepatocytes. In obese KK-Ay mice, bixin treatment suppressed the development of hyperlipidemia and hepatic lipid accumulation. In the livers of bixin-treated mice, the mRNA levels of PPARα target genes related to fatty acid oxidation were up-regulated. Moreover, bixin treatment also improved obesity-induced dysfunctions of carbohydrate metabolism, such as hyperglycemia, hyperinsulinemia, and hypoadiponectinemia. Glucose tolerance test and insulin tolerance test revealed that glucose intolerance and insulin resistance in KK-Ay obese mice were attenuated by the treatment with bixin. These results indicate that bixin acts as a food-derived agonist of PPARα, and bixin treatment is useful for the management of obesity-induced metabolic dysfunctions in mice.

The mechanism underlying the central glucagon-induced hyperglycemia and anorexia in chicks.

We investigated the mechanism underlying central glucagon-induced hyperglycemia and anorexia in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of glucagon in chicks induced hyperglycemia and anorexia from 30 min after administration. However, the plasma insulin level did not increase until 90 min after glucagon administration, suggesting that glucose-stimulated insulin secretion from pancreatic beta cells may be suppressed by central glucagon. The plasma corticosterone concentration significantly increased from 30 min to 120 min after administration, suggesting that central glucagon activates the hypothalamic pituitary adrenal (HPA) axis in chicks. However, central administration of corticotropin-releasing factor (CRF), which activates the HPA axis in chicken hypothalamus, significantly reduced not only food intake but also plasma glucose concentration, suggesting that CRF and the activation of the HPA axis are related to the glucagon-induced anorexia but not hyperglycemia in chicks. Phentolamine, an α-adrenergic receptor antagonist, significantly attenuated the glucagon-induced hyperglycemia, suggesting that glucagon induced hyperglycemia at least partly via α-adrenergic neural pathway. Co-administration of phentolamine and α-helical CRF, a CRF receptor antagonist, significantly attenuated glucagon-induced hyperglycemia and anorexia. It is therefore likely that central administration of glucagon suppresses food intake at least partly via CRF-induced anorexigenic pathway in chicks.

Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice.

Tiliroside contained in several dietary plants, such as rose hips, strawberry and raspberry, is a glycosidic flavonoid and possesses anti-inflammatory, antioxidant, anticarcinogenic and hepatoprotective activities. Recently, it has been reported that the administration of tiliroside significantly inhibited body weight gain and visceral fat accumulation in normal mice. In this study, we evaluated the effects of tiliroside on obesity-induced metabolic disorders in obese-diabetic KK-A(y) mice. In KK-A(y) mice, the administration of tiliroside (100 mg/kg body weight/day) for 21 days failed to suppress body weight gain and visceral fat accumulation. Although tiliroside did not affect oxygen consumption, respiratory exchange ratio was significantly decreased in mice treated with tiliroside. In the analysis of metabolic characteristics, it was shown that plasma insulin, free fatty acid and triglyceride levels were decreased, and plasma adiponectin levels were increased in mice administered tiliroside. The messenger RNA expression levels of hepatic adiponectin receptor (AdipoR)-1 and AdipoR2 and skeletal muscular AdipoR1 were up-regulated by tiliroside treatment. Furthermore, it was indicated that tiliroside treatment activated AMP-activated protein kinase in both the liver and skeletal muscle and peroxisome proliferator-activated receptor α in the liver. Finally, tiliroside inhibited obesity-induced hepatic and muscular triglyceride accumulation. These findings suggest that tiliroside enhances fatty acid oxidation via the enhancement adiponectin signaling associated with the activation of both AMP-activated protein kinase and peroxisome proliferator-activated receptor α and ameliorates obesity-induced metabolic disorders, such as hyperinsulinemia and hyperlipidemia, although it does not suppress body weight gain and visceral fat accumulation in obese-diabetic model mice.

Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways.

Peroxisome proliferator-activated receptors (PPARs) control energy homeostasis. In this study, we showed that farnesol, a naturally occurring ligand of PPARs, could ameliorate metabolic diseases. Obese KK-Ay mice fed a high-fat diet (HFD) containing 0.5% farnesol showed significantly decreased serum glucose level, glucosuria incidence, and hepatic triglyceride contents. Farnesol-containing HFD upregulated the mRNA expressions of PPARα target genes involved in fatty acid oxidation in the liver. On the other hand, farnesol was not effective in upregulating the mRNA expressions of PPARγ target genes in white adipose tissues. Experiments using PPARα-deficient [(-/-)] mice revealed that the upregulation of fatty acid oxidation-related genes required PPARα function, but the suppression of hepatic triglyceride accumulation was partially PPARα-dependent. In hepatocytes isolated from the wild-type and PPARα (-/-) mice, farnesol suppressed triglyceride synthesis. In luciferase assay, farnesol activated both PPARα and the farnesoid X receptor (FXR) at similar concentrations. Moreover, farnesol increased the mRNA expression level of a small heterodimer partner known as one of the FXR target genes and decreased those of sterol regulatory element-binding protein-1c and fatty acid synthase in both the wild-type and PPARα (-/-) hepatocytes. These findings suggest that farnesol could improve metabolic abnormalities in mice via both PPARα-dependent and -independent pathways and that the activation of FXR by farnesol might contribute partially to the PPARα-independent hepatic triglyceride content-lowering effect. To our knowledge, this is the first study on the effect of the dual activators of PPARα and FXR on obesity-induced metabolic disorders.

Activation of peroxisome proliferator-activated receptor-alpha stimulates both differentiation and fatty acid oxidation in adipocytes.

Peroxisome proliferator-activated receptor-α (PPARα) is a dietary lipid sensor, whose activation results in hypolipidemic effects. In this study, we investigated whether PPARα activation affects energy metabolism in white adipose tissue (WAT). Activation of PPARα by its agonist (bezafibrate) markedly reduced adiposity in KK mice fed a high-fat diet. In 3T3-L1 adipocytes, addition of GW7647, a highly specific PPARα agonist, during adipocyte differentiation enhanced glycerol-3-phosphate dehydrogenase activity, insulin-stimulated glucose uptake, and adipogenic gene expression. However, triglyceride accumulation was not increased by PPARα activation. PPARα activation induced expression of target genes involved in FA oxidation and stimulated FA oxidation. In WAT of KK mice treated with bezafibrate, both adipogenic and FA oxidation-related genes were significantly upregulated. These changes in mRNA expression were not observed in PPARα-deficient mice. Bezafibrate treatment enhanced FA oxidation in isolated adipocytes, suppressing adipocyte hypertrophy. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα was recruited to promoter regions of both adipogenic and FA oxidation-related genes in the presence of GW7647 in 3T3-L1 adipocytes. These findings indicate that the activation of PPARα affects energy metabolism in adipocytes, and PPARα activation in WAT may contribute to the clinical effects of fibrate drugs.

Diosgenin, the main aglycon of fenugreek, inhibits LXRα activity in HepG2 cells and decreases plasma and hepatic triglycerides in obese diabetic mice.

Trigonella foenum-graecum (fenugreek) can ameliorate dyslipidemia, but the detailed mechanism is unclear. In this study, we examined the effects of fenugreek on hepatic lipid metabolism, particularly lipogenesis, which is enhanced in obesity and diabetes, in diabetic obese KK-Ay mice. KK-Ay mice were fed a control high-fat diet (HFD; 60% of energy as fat) (C group) or an HFD containing 0.5% or 2% fenugreek (0.5F and 2.0F groups, respectively) for 4 wk. Hepatic and plasma TG and mRNA expression levels of lipogenic genes were lower in the 2.0F group at 4 wk (P < 0.05), but not in the 0.5F group, than in the C group. The hydrolyzed saponin fraction, but not the saponin fraction per se, in fenugreek inhibited the accumulation of TG in HepG2 cells. We fractionated the hydrolyzed saponin into 15 fractions by HPLC and examined the effect of these fractions on TG accumulation in HepG2 cells. Fraction 11 inhibited TG accumulation in HepG2 cells and we determined by liquid chromatography tandem MS that the active substance contained in fraction 11 is diosgenin. Diosgenin (5 and 10 µmol/L) inhibited the accumulation of TG and the expression of lipogenic genes in HepG2 cells. Moreover, diosgenin inhibited the transactivation of liver-X-receptor-α, as measured using a luciferase assay system and by gel mobility shift assay. These findings suggest that fenugreek ameliorates dyslipidemia by decreasing the hepatic lipid content in diabetic mice and that its effect is mediated by diosgenin. Fenugreek, which contains diosgenin, may be useful for the management of diabetes-related hepatic dyslipidemias.

Diosgenin present in fenugreek improves glucose metabolism by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues.

In obesity, adipocyte hypertrophy and chronic inflammation in adipose tissues cause insulin resistance and type-2 diabetes. Trigonella foenum-graecum (fenugreek) can ameliorate hyperglycemia and diabetes. However, the effects of fenugreek on adipocyte size and inflammation in adipose tissues have not been demonstrated. In this study, we determined the effects of fenugreek on adipocyte size and inflammation in adipose tissues in diabetic obese KK-Ay mice, and identified the active substance in fenugreek. Treatment of KK-Ay mice with a high fat diet supplemented with 2% fenugreek ameliorated diabetes. Moreover, fenugreek miniaturized the adipocytes and increased the mRNA expression levels of differentiation-related genes in adipose tissues. Fenugreek also inhibited macrophage infiltration into adipose tissues and decreased the mRNA expression levels of inflammatory genes. In addition, we identified diosgenin, a major aglycone of saponins in fenugreek to promote adipocyte differentiation and to inhibit expressions of several molecular candidates associated with inflammation in 3T3-L1 cells. These results suggest that fenugreek ameliorated diabetes by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues, and its effects are mediated by diosgenin. Fenugreek containing diosgenin may be useful for ameliorating the glucose metabolic disorder associated with obesity.

Functional food targeting the regulation of obesity-induced inflammatory responses and pathologies.

Obesity is associated with a low-grade systemic chronic inflammatory state, characterized by the abnormal production of pro- and anti-inflammatory adipocytokines. It has been found that immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Obesity-induced inflammation is considered a potential mechanism linking obesity to its related pathologies, such as insulin resistance, cardiovascular diseases, type-2 diabetes, and some immune disorders. Therefore, targeting obesity-related inflammatory components may be a useful strategy to prevent or ameliorate the development of such obesity-related diseases. It has been shown that several food components can modulate inflammatory responses in adipose tissue via various mechanisms, some of which are dependent on peroxisome proliferator-activated receptor gamma (PPARgamma), whereas others are independent on PPARgamma, by attenuating signals of nuclear factor-kappaB (NF-kappaB) and/or c-Jun amino-terminal kinase (JNK). In this review, we introduce the beneficial effects of anti-inflammatory phytochemicals that can help prevent obesity-induced inflammatory responses and pathologies.

Diosgenin attenuates inflammatory changes in the interaction between adipocytes and macrophages.

Obese adipose tissues are characterized by the enhanced infiltration of macrophages. It is considered that the paracrine loop involving monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and the free fatty acid between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes and insulin resistance in obese adipose tissues. Diosgenin, a saponin aglycon found in a variety of plants, has anti-inflammatory properties. In the present study, we examined the effect of diosgenin on the inflammatory changes in the interaction between adipocytes and macrophages. A coculture of 3T3-L1 adipocytes and RAW 264 macrophages markedly enhanced the production of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nitric oxide compared with the sum of their single cultures; however, treatment with diosgenin inhibited the production of these proinflammatory mediators. Diosgenin also suppressed the inflammation in RAW 264 macrophages that was induced by the conditioned medium derived from 3T3-L1 adipocytes. Furthermore, diosgenin inhibited the conditioned medium-induced degradation of inhibitor kappaB and the phosphorylation of c-jun N-terminal kinase in macrophages. These results indicate that diosgenin exhibits anti-inflammatory properties in the interaction of adipocytes and macrophages by inhibiting the inflammatory signals in macrophages. Diosgenin may be useful for ameliorating the inflammatory changes in obese adipose tissues.

Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPARgamma activation.

Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. The uptake is dependent on adipocyte differentiation, which is controlled at mRNA transcription level. The peroxisome proliferator-activated receptor (PPAR), a ligand-regulated nuclear receptor, is involved in the differentiation. Many food-derived compounds serve as ligands to activate or inactivate PPAR. In this study, we demonstrated that bixin and norbixin (annatto extracts) activate PPARgamma by luciferase reporter assay using GAL4-PPAR chimera proteins. To examine the effects of bixin on adipocytes, 3T3-L1 adipocytes were treated with bixin or norbixin. The treatment induced mRNA expression of PPARgamma target genes such as adipocyte-specific fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and adiponectin in differentiated 3T3-L1 adipocytes and enhanced insulin-dependent glucose uptake. The observations indicate that bixin acts as an agonist of PPARgamma and enhances insulin sensitivity in 3T3-L1 adipocytes, suggesting that bixin is a valuable food-derived compound as a PPAR ligand to regulate lipid metabolism and to ameliorate metabolic syndrome.

Luteolin, a food-derived flavonoid, suppresses adipocyte-dependent activation of macrophages by inhibiting JNK activation.

Interaction between adipocytes and macrophages contributes to the development of insulin resistance in obese adipose tissues. In this study, we examined whether luteolin, food-derived flavonoid, could suppress the production of inflammatory mediators of the interaction between adipocytes and macrophages. Experiments using a coculture system of adipocytes and macrophages showed that luteolin suppressed the production of inflammatory mediators. In addition, activated macrophages were targets for the suppressive effect of luteolin. Luteolin inhibited the phosphorylation of JNK and suppressed the production of inflammatory mediators in the activated macrophages. The findings indicate that luteolin can inhibit the interaction between adipocytes and macrophages to suppress the production of inflammatory mediators, suggesting that luteolin is a valuable food-derived compound for the treatment of metabolic syndrome.

Dehydroabietic acid, a diterpene, improves diabetes and hyperlipidemia in obese diabetic KK-Ay mice.

Terpenoids, which are contained in a large number of dietary and herbal plants, have many biological effects. In this study, the effects of dehydroabietic acid (DAA), a diterpene, on glucose and lipid metabolism were examined using obese diabetic KK-Ay mice. We showed here that DAA treatment decreased not only plasma glucose and insulin levels but also plasma triglyceride (TG) and hepatic TG levels. To examine the mechanism underlying the effects of DAA, the production of inflammatory cytokines was measured. It was shown that the DAA treatment suppressed the production of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNFalpha) (proinflammatory cytokines) and increased that of adiponectin (an anti-inflammatory cytokine). As a result of the changes in the production of inflammatory cytokines caused by the DAA treatment, the accumulation of macrophages in adipose tissues was reduced. These results indicate that treatment with DAA improves the levels of plasma glucose, plasma insulin, plasma TG, and hepatic TG through the decrease in the macrophage infiltration into adipose tissues, suggesting that DAA is a useful food-derived compound for treating obesity-related diseases.

Genome science of lipid metabolism and obesity.

Abnormalities in lipid metabolism cause obesity leading to metabolic syndrome. Thus, improvement of the abnormalities is significant for the treatment of metabolic syndrome. Nuclear receptors activated by specific ligands regulate lipid metabolism at the genomic level. The expression of lipid metabolism-related enzymes is increased or decreased by the activity of various nuclear receptors. The regulation of enzyme expression is mediated by specific response elements to each nuclear receptor in promoters of target genes. Many food factors acting as agonists or antagonists control the activities of nuclear receptors. Here, we provide several examples of food factors acting as agonists or antagonists, which are useful for the management of obesity accompanied by lipid metabolism abnormalities.

Dietary regulation of nuclear receptors in obesity-related metabolic syndrome.

In Western culture, excess visceral fat accumulation or obesity has reached epidemic proportions, resulting in metabolic syndrome. However, more than 10 years of research has shown that adipocytes also function as endocrine cells that release various bioactive substances, so called "adipocytokines or adipokines", that play a major role in the regulation of food intake, insulin sensitivity, energy metabolism, and the vascular microenvironment. Adiponectin, an adipocytokine, is considered to improve insulin sensitivity. Recently, monocyte chemoattractant protein (MCP)-1 has been reported to be a novel adipocytokine involved in the development of obesity-associated insulin resistance and atherosclerosis. Nuclear receptors, especially peroxisome proliferator-activated receptor-alpha (PPAR alpha) and PPAR gamma are ligand-activated transcription factors that regulate the metabolism of glucose and lipids. PPAR gamma is strongly expressed in adipocytes and plays a significant role in the transcriptional activation of adipocytokines including adiponectin. PPAR alpha, another PPAR isoform, is involved in the control of lipid metabolism in the liver and skeletal muscle. PPAR alpha activation causes lipid clearance via beta-oxidation enhancement. We showed that various dietary terpenoids and other natural ingredients regulate the transcription of PPAR target genes, induces the expression and secretion of adiponectin, and inhibits those of MCP-1 in adipocytes and beta-oxidation in liver. These findings indicate that dietary factor acts as an agonist of PPARs and is a valuable medical and food component for the gradual improvement of metabolic syndrome.

Dehydroabietic acid, a phytochemical, acts as ligand for PPARs in macrophages and adipocytes to regulate inflammation.

Obesity is characterized by an enhanced infiltration of macrophages to adipose tissues, which is closely associated with the low-grade inflammatory state and obesity-related pathologies such as type 2 diabetes and cardiovascular diseases. We showed here that dehydroabietic acid (DAA) is a potent PPARalpha/gamma dual activator. Furthermore, we examined the anti-inflammatory effects of DAA in stimulated macrophages and in the coculture of macrophages and adipocytes. DAA significantly suppressed the production of proinflammatory mediators such as MCP-1, TNF-alpha, and NO in stimulated RAW 264 macrophages and in the coculture of RAW 264 macrophages and 3T3-L1 adipocytes. These results suggest that DAA is a valuable medicinal and food component for improving inflammatory changes associated with obesity-related diabetes.