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Purpose: Angiopoietin-like proteins (ANGPTLs) 3, 4, and 8 reportedly contribute to progression of metabolic disease, a risk factor for cardiovascular disease (CVD). The purpose of this study was to investigate whether circulating ANGPTL levels are associated with CVD risk after adjustment for potential confounding factors., Methods: We conducted a single center, cross-sectional study of 988 Japanese subjects undergoing routine health checks. Serum ANGPTL3, 4, and 8 levels were measured using an enzyme-linked immunosorbent assay. Using multiple regression analysis we evaluated potential association of circulating ANGPTL3, 4, and 8 levels with general medical status including age, sex, smoking, drinking, obesity, hypertension, impaired glycometabolism, dyslipidemia, hyperuricemia, hepatic impairment, chronic kidney disease, anemia, cardiac abnormality, and inflammation., Results: Circulating ANGPTL3 levels were relatively high in health-related categories of hepatic impairment and inflammation. Circulating ANGPTL4 levels were also significantly high in impaired glycometabolism or hepatic impairment but decreased in inflammation. Finally, increased ANGPTL8 levels were observed in obesity, impaired glycometabolism and dyslipidemia. Particularly, increased levels of circulating ANGPTL8 were positively correlated with circulating triglycerides and LDL-cholesterol levels and inversely correlated with circulating HDL-cholesterol levels., Conclusions: Circulating ANGPTL3, 4, and 8 levels reflect some risk factors for CVD development.

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitors are the most frequently prescribed oral hypoglycemic agents in Japan. Although a relationship between the efficacy of DPP-4 inhibitors and the body mass index (BMI) has been reported, this relationship is controversial. We investigated whether the BMI value affects the glucose-lowering efficacy of sitagliptin in obese Japanese patients with type 2 diabetes. Methods One hundred sixty-two outpatients with inadequate glycemic control were divided into four groups based on their baseline BMI values. They were then treated with sitagliptin (a DPP-4 inhibitor) for 3 months and followed-up for 12 months. Results Sitagliptin significantly reduced the hemoglobin A1c level (HbA1c: -0.71±0.55%) after 3 months, and continued to reduce the HbA1c level until 12 months. There was no significant difference in the efficacy of sitagliptin among the four BMI groups. A multiple linear regression analysis indicated that the factors contributing to the change in the HbA1c level were the baseline level of HbA1c and the homeostasis model assessment of β-cell function (HOMA-β). In terms of the relationship between the baseline BMI value and the efficacy of sitagliptin treatment, the number of patients who responded to sitagliptin treatment after 3 months was lowest in the group of patients with the highest BMI values. A multiple logistic regression analysis revealed that the baseline HOMA-β function and HbA1c level and a baseline BMI value of ≥30 kg/m 2 significantly contributed to the response to sitagliptin treatment. Conclusion The results indicated that sitagliptin treatment was effective in controlling glucose metabolism disorder in obese Japanese patients with type 2 diabetes. However, the efficacy of sitagliptin treatment might be attenuated in severely obese patients, such as those with a BMI value of ≥30 kg/m 2 .

Purified milk sphingomyelin (SM) was obtained from lipid concentrated butter serum (LC-BS) by successive separations involving solvent fractionation, selective saponification, and silicic acid column chromatography. The SM obtained was given to obese/diabetic KK-A(y) mice and wild-type C57BL/6J mice. SM supplementation significantly increased fecal lipids paralleled with a decrease in non-HDL cholesterol levels in the serum and neutral lipids and in cholesterol levels in the livers of KK-A(y) mice. The reduction of liver lipid levels also resulted in a decrease in the total fatty acid content of the KK-A(y) mice livers, while n-3 fatty acids derived from the conversion of α-linolenic acid (18:3n-3) increased due to SM supplementation. In contrast to the KK-A(y) mice, little change in the serum and liver lipids was observed in wild-type C57BL/6J mice. The present study suggests that SM may be effective only in subjects with metabolic disorders.

Background: The objective of this study was to establish a new sandwich based enzyme linked immunosorbent assay (ELISA) for measuring the protein mass of human hepatic triacylglyceride lipase (HTGL)., Method: Two mouse monoclonal antibodies raised against human HTGL were used for the sandwich ELISA. The post-heparin plasma (PHP) samples obtained at a heparin dose of 50 unit/kg from 124 normolipidemic subjects were used for this ELISA., Results: The dynamic assay range of the developed ELISA for the HTGL was from 0.47 to 30 ng/ml. The CV was <7% in both intra- and inter-assays, and it did not cross-react with lipoprotein lipase or endothelial lipase (EL). The HTGL concentration in PHP showed a strong correlation with HTGL activity [n=121, r=0.778, p<0.001]. There was a weak relation of HTGL concentration against high-density lipoprotein cholesterol (HDL-C) [n=123, r=-0.229, p=0.011] but no relations against total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), small dense LDL, remnant like particles cholesterol (RLP-C) and RLP-TG were confirmed. Interestingly, a weak but positive correlation between HTGL concentration and EL concentration was shown [n=122, p=0.013, r=0.224]., Conclusion: These results indicate that this new sandwich ELISA for measuring HTGL concentration in PHP can be applied in a daily clinical practice., (© 2013 Elsevier B.V. All rights reserved.)

Stearoyl-coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. Recently, SCD1 down-regulation has been implicated in the prevention of obesity, and the improvement of insulin and leptin sensitivity. In this study, we examined the effect of fucoxanthin, a marine carotenoid, on hepatic SCD1 in obese mouse models of hyperleptinemia KK-A(y) and leptin-deficiency ob/ob. In KK-A(y) mice, providing a diet containing 0.2 % fucoxanthin for 2 weeks markedly suppressed SCD1 mRNA and protein expressions in the liver. The fatty acid composition of liver lipids was also affected by an observed decrease in the ratio of oleic acid to stearic acid. Furthermore, serum leptin levels were significantly decreased in hyperleptinemia KK-A(y) mice after 2 weeks of fucoxanthin feeding. However, the suppressive effects of fucoxanthin on hepatic SCD1 and body weight gain were not observed in ob/ob mice. These results show that fucoxanthin down-regulates SCD1 expression and alters fatty acid composition of the liver via regulation of leptin signaling in hyperleptinemia KK-A(y) mice but not in leptin-deficient ob/ob mice.

Background: Fucoxanthin is a xanthophyll present in brown seaweeds and has several beneficial effects, including anti-obesity and anti-diabetic effects. However, we and another group previously observed that fucoxanthin increases serum cholesterol levels in rodents. Cholesterol is an important component of cell membranes and biosynthesis of bile acids. Serum cholesterol levels are also closely associated with atherosclerosis. Therefore, we sought to identify the mechanism underlying the increase in serum cholesterol levels by fucoxanthin., Methods: Diabetic/obese KK-A(y) mice were fed a diet containing 0.2% fucoxanthin for 4 weeks. The mice were sacrificed, and total blood samples were collected for the measurement of serum total cholesterol, HDL-cholesterol and non-HDL-cholesterol levels. Cholesterol content in tissues was also analyzed. Real-time PCR and Western blotting were performed to determine hepatic mRNA and protein expression of genes involved in cholesterol metabolism, respectively., Results: Dietary fucoxanthin significantly increased serum HDL and non-HDL cholesterol levels, and reduced hepatic cholesterol content. In liver, the expression of SREBP1, SREBP2 and their target genes involved in cholesterol biosynthesis significantly increased and tended to increase in the fucoxanthin-fed mice, respectively. In contrast, hepatic levels of LDLR and SR-B1 proteins which is important factors for LDL-cholesterol and HDL-cholesterol uptake in the liver from serum, decreased to 60% and 80% in the fucoxanthin-fed mice, respectively, compared with the control mice. Further, we found that dietary fucoxanthin significantly increased the mRNA expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which enhances intracellular degradation of LDLR in lysosomes., Conclusions: Fucoxanthin increased HDL-cholesterol and non-HDL-cholesterol levels in KK-A(y) mice by inducing SREBP expression and reduced cholesterol uptake in the liver via down-regulation of LDLR and SR-B1, resulted in increased serum cholesterol in the mice.

n-3 Polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and taurine are functional compounds abundantly present in seafoods. In this study, we examined the combined effects of EPA- and DHA-rich fish oil and taurine on white adipose tissue (WAT) weight and blood glucose levels in diabetic/obese KK-A(y) mice. After a 4-wk administration of experimental diets (soybean oil or fish oil, supplemented with 0%, 2%, or 4% taurine), the increase in WAT weight of the mice fed the "fish oil + 4% taurine" diet was significantly suppressed compared to the "soybean oil + 4% taurine" and "fish oil only" diets. Serum triglycerides, free fatty acids, and total cholesterol levels decreased by fish oil administration. In addition, fish oil and taurine increased the activity of acyl-CoA oxidase, which is the rate-limiting enzyme of peroxisomal β-oxidation, increased in the liver of KK-A(y) mice. The activity of fatty acid synthase decreased by fish oil diets. Furthermore, blood glucose and insulin levels were significantly lower in the mice fed fish oil than in the soybean oil-fed mice. In fish oil + 4% taurine group, hyperglycemia and hyperinsulinemia were effectively improved in KK-A(y) mice compared to the fish oil only groups. In particular, the combination of fish oil and taurine enhanced the glucose transporter 4 (GLUT4) distribution in the plasma membrane of muscle tissue. These results suggest that EPA- and DHA-rich fish oil, especially in combination with taurine, exhibits preventive effects on WAT weight gain and hyperglycemia in diabetic/obese KK-A(y) mice., (© 2012 Institute of Food Technologists®)

Based on previous research findings, a capsule was developed containing n-3 polyunsaturated fatty acid rich scallop phospholipids (PLs) with an incorporation of brown seaweed (Undaria pinnatifida) lipids (ULs) containing fucoxanthin. The antiobesity effects of the capsules were evaluated with an animal model using 3-wk-old male KK-A(y) mice. Each group received different combinations of lipid (UL, PL, UL + PL, or UL + PL capsule) either incorporated into the diet or into drinking water. Animals were sacrificed after a 4-wk experimental feeding period, and adipose tissues and organs were dissected and weighed. Blood samples were obtained to determine plasma lipid profiles. Uncoupling protein 1 (UCP1) mRNA expression levels were determined by real-time polymerase chain reaction analysis, and UCP1 expression was determined by western blotting analysis. Treatment with either UL alone or UL + PL (capsule) through drinking water resulted in a significant reduction in body weight, compared to the control group. The total white adipose tissue weight of mice fed the UL + PL capsule in drinking water was significantly reduced. Both UCP1 and UCP1 mRNA expression in epididymal fat from mice fed the capsule were significantly higher than in the control group. These results suggest that incorporation of UL into scallop-derived PL by means of capsulation may lead to an additive increase in the antiobesity properties of these bioactive lipids.

Fucoxanthin, a marine carotenoid found in edible brown seaweeds, attenuates white adipose tissue (WAT) weight gain and hyperglycemia in diabetic/obese KK-A(y) mice, although it does not affect these parameters in lean C57BL/6J mice. In perigonadal and mesenteric WATs of KK-A(y) mice fed fucoxanthin, mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), which are considered to induce insulin resistance, were markedly reduced compared to control mice. In contrast to KK-A(y) mice, fucoxanthin did not alter MCP-1 and TNF-α mRNA expression levels in the WAT of lean C57BL/6J mice. Interleukin-6 (IL-6) and plasminogen activator inhibitor-1 mRNA expression levels in WAT were also decreased by fucoxanthin in KK-A(y) mice. In differentiating 3T3-F442A adipocytes, fucoxanthinol, which is a fucoxanthin metabolite found in WAT, attenuated TNF-α-induced MCP-1 and IL-6 mRNA overexpression and protein secretion into the culture medium. In addition, fucoxanthinol decreased TNF-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression in RAW264.7 macrophage-like cells stimulated by palmitic acid. These findings indicate that fucoxanthin regulates mRNA expression of inflammatory adipocytokines involved in insulin resistance, iNOS, and COX-2 in WAT and has specific effects on diabetic/obese KK-A(y) mice, but not on lean C57BL/6J mice., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism., Research Design and Methods: We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA(+/-)) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes., Results: BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1alpha and PPARdelta. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA(+/-) mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1alpha and PPARdelta and mitochondrial content in cultured myocytes., Conclusions: The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.

Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.

Measurement of brachial-ankle pulse wave velocity (baPWV) is recognized as a simple and practical method for assessing arterial stiffness. We determined whether the baPWV of adolescents is affected by obesity and its associated metabolic risk variables. A cross-sectional sample of 754 apparently healthy adolescents (383 men and 371 women), aged 15-17 years, was recruited for this study. baPWV was measured by a simple automatic oscillometric technique. Adiposity measures, blood pressure, serum lipoproteins, fasting glucose and insulin were evaluated. The baPWV of the adolescents was significantly higher in men than in women and increased with age in both genders. After being statistically adjusted for age and gender, baPWV was significantly correlated with body mass index, percent body fat, waist-to-height ratio, systolic and diastolic blood pressures, mean arterial pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), atherogenic index, glucose, insulin, and homoeostasis model assessment of insulin resistance (HOMA-IR). In the multivariate regression analysis, mean arterial pressure, atherogenic index, HOMA-IR, systolic blood pressure and age were found to be significant determinants of baPWV (P<0.001). An increasing number of clustered risk variables, including high values (>gender-specific top quartiles) of waist-to-height ratio, mean arterial pressure, atherogenic index and HOMA-IR showed a graded association with baPWV (P<0.001 for trend). These results suggest that obesity and its associated metabolic abnormalities are important factors in the increased baPWV of adolescents and that baPWV may be useful in investigating early arterial wall changes in this population.

Fucoxanthin has a unique structure including an unusual allenic bond and 5, 6-monoepoxide in its molecule. We found that abdominal white adipose tissue (WAT) weights of rats and mice fed fucoxanthin were significantly lower than those fed a control diet. The daily intake of fucoxanthin in mice also caused a significant reductions of body weight. Clear signals of uncoupling protein 1 (UCP1) and its mRNA were detected by Western and Northern blot analyses in abdominal WAT in mice fed fucoxanthin, although there is little expression of UCP1 in WAT in mice fed a control diet. UCP1 expression in WAT by fucoxanthin intake leads to oxidation of fatty acids and heat production in WAT mitochondria. Substrate oxidation can directly reduce WAT in animals. Fucoxanthin intake also significantly reduced blood glucose and plasma insulin. Furthermore, feeding fucoxanthin significantly increased the level of hepatic docosahexaenoic acid (DHA), a most important n-3 functional polyunsaturated fatty acid in biological systems. These multi-functionalities of fucoxanthin indicate that it is an important bioactive carotenoid that is beneficial for the prevention of the metabolicsyndrome.

Fucoxanthin is a marine carotenoid found in edible brown seaweeds. We previously reported that dietary fucoxanthin attenuates the weight gain of white adipose tissue (WAT) of diabetic/obese KK- A(y) mice. In this study, to evaluate the antiobesity and antidiabetic effects of fucoxanthin and fish oil, we investigated the effect on the WAT weight, blood glucose, and insulin levels of KK- A(y) mice. Furthermore, the expression level of uncoupling protein 1 (UCP1) and adipokine mRNA in WAT were measured. After 4 weeks of feeding, 0.2% fucoxanthin in the diet markedly attenuated the gain of WAT weight in KK- A(y) mice with increasing UCP1 expression compared with the control mice. The WAT weight of the mice fed 0.1% fucoxanthin and 6.9% fish oil was also significantly lower than that of the mice fed fucoxanthin alone. In addition, 0.2% fucoxanthin markedly decreased the blood glucose and plasma insulin concentrations in KK- A(y) mice. The mice fed with the combination diet of 0.1% fucoxanthin and fish oil also showed improvements similar to that of 0.2% fucoxanthin. Leptin and tumor necrosis factor (TNFalpha) mRNA expression in WAT were significantly down-regulated by 0.2% fucoxanthin. These results suggest that dietary fucoxanthin decreases the blood glucose and plasma insulin concentration of KK- A(y) along with down-regulating TNFalpha mRNA. In addition, the combination of fucoxanthin and fish oil is more effective for attenuating the weight gain of WAT than feeding with fucoxanthin alone.

This study examined the effect of dietary fucoxanthin or fucoxanthinol on the amount of docosahexaenoic acid (DHA) in the liver of KKAy mice, a model for obese/type II diabetes. In the first experiment, mice were fed diets containing crude fucoxanthin or glyceroglycolipid for 4 weeks. Results showed a significant increase in the level of DHA in mice fed 0.53% crude fucoxanthin, from 2.3% in control mice to 5.1% of fatty acid composition of total liver lipids. On the other hand, in mice fed crude glyceroglycolipid, the level of DHA as a proportion of total liver fatty acids remained unchanged. To clarify the enhancement of hepatic DHA, in the second experiment, KKAy mice were fed a diet containing purified fucoxanthin or its deacetylated derivative, fucoxanthinol. Results from a quantitative analysis using an internal standard showed that in mice fed 0.2% fucoxanthin, the amount of hepatic DHA was 2-fold higher than in control mice, whereas DHA levels in the small intestine remained unchanged. Furthermore, 0.2% fucoxanthinol led to 1.8- and 1.2-fold increases in the amount of hepatic DHA and arachidonic acid compared to control mice, respectively. These results indicate for the first time that dietary fucoxanthin and fucoxanthinol enhance the amount of DHA in the liver of KKAy mice.

Dietary effects of medium-chain triacylglycerols (MCT) and fucoxanthin (Fc) on abdominal fat weight were determined using KK-Ay obese mouse. Experimental diet contained MCT(0.9%), Fc (0.1%), or MCT (0.9%) +Fc (0.1%). The abdominal fat weight of mice fed with Fc was significantly lower than that of mice fed with MCT. Uncoupling protein 1 (UCP1), a key molecule for metabolic thermogenesis, was clearly expressed in the white adipose tissue (WAT) of mice fed Fc, but little expression in that of the mice fed MCT. The anti-obesity effect of Fc was increased by mixing Fc with MCT. This increase would be due to the increase in the absorption rate of Fc by MCT.

Mitochondrial uncoupling protein 1 (UCP1) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis to avoid an excess of fat accumulation. However, there is little BAT in adult humans. Therefore, UCP1 expression in tissues other than BAT is expected to reduce abdominal fat. Here, we show reduction of abdominal white adipose tissue (WAT) weights in rats and mice by feeding lipids from edible seaweed, Undaria pinnatifida. Clear signals of UCP1 protein and mRNA were detected in WAT of mice fed the Undaria lipids, although there is little expression of UCP1 in WAT of mice fed control diet. The Undaria lipids mainly consisted of glycolipids and seaweed carotenoid, fucoxanthin. In the fucoxanthin-fed mice, WAT weight significantly decreased and UCP1 was clearly expressed in the WAT, while there was no difference in WAT weight and little expression of UCP1 in the glycolipids-fed mice. This result indicates that fucoxanthin upregulates the expression of UCP1 in WAT, which may contribute to reducing WAT weight.

Dietary supplementation of conjugated linoleic acids (CLA) is known to have some beneficial effects such as anti-carcinogenic and anti-obesity effects in several animal species, while it also induces insulin resistance and fatty liver, especially in mice. To explore the possible factors responsible for the CLA-induced insulin resistance, we examined the plasma and mRNA expression levels of several adipocytokines, which are likely involved in the regulation of insulin sensitivity, in normal C5 7BL, mildly obese/diabetic KK and morbidly obese/diabetic KKAy mice. Feeding a diet supplemented with 0.5%, CLA oil consisting of 30.5/% c9, t11-CLA and 28.9% t10, c12-CLA for 4 wk resulted in a decrease in white adipose tissue (WAT), an increase in liver weight with excess accumulation of triglyceride, and insulin resistance associated with hyperglycemia and hyperinsulinemia. The plasma and WAT mRNA levels of leptin were higher in KK and KKAy mice than C57BI. mice, whereas those of adiponectin were higher in C5 7BL mice. CLA-feeding decreased the levels of leptin, adiponectin and resistin, especially in KK and KKAy mice. In contrast, tumor necrosis factor-alpha (TNFalpha) mRNA levels were higher in KK and KKAy mice than C57BL mice, and were increased by CLA feeding. The present results thus indicate that CLA feeding promotes insulin resistance in obese/diabetic mice by at least inverse regulation of leptin and adiponectin, and TNFalpha, adipocytokines known to either ameliorate or deteriorate insulin sensitivity, respectively.