Effect of intermittent and continuous caloric restriction on Sirtuin1 concentration depends on sex and body mass index.

BACKGROUND & AIMS: The favorable effect of caloric restriction (CR) on health span is well known and partly mediated by the sirtuin system. Sirtuin1, a regulator of energy homeostasis in response to nutrient availability, is activated by CR. We therefore investigated effects of two different CR regimens on Sirtuin1 concentrations. METHODS & RESULTS: The study included 112 abdominally obese subjects, randomized to intermittent or continuous CR for 1 year. Blood samples and anthropometric measures were collected at baseline and after 12 months. Sirtuin1 concentrations were measured by ELISA. Sirtuin1 correlated significantly to BMI at baseline (r = .232, p = 0.019). Mean reduction in body-weight was 8.0 and 9.0 kg after intermittent and continuous CR, respectively. After 1 year, no significant between-group differences in Sirtuin1 levels were observed according to regimen (p = 0.98) and sex (p = 0.41). An increase in median Sirtuin1 concentrations (pg/mL) [25, 75 percentiles] from baseline was observed after intermittent CR in the total population (884 [624, 1285] vs.762 [530, 1135]; p = 0.041), most marked in men (820 [623, 1250] vs. 633 [524, 926]; p = 0.016). Improvement in BMI after 1 year correlated to Sirtuin1 changes, but varied according to sex. In women, Spearman's rho = .298, p = 0.034, with stronger correlation in the intermittent CR group (r = .424, p = 0.049). In men, there was an inverse relation to Sirtuin1 changes, only in the intermittent CR group (r = -.396, p = 0.045). CONCLUSIONS: Effects on Sirtuin1 concentrations after 1 year of CR are sex and BMI-related. Intermittent CR regimen affected Sirtuin1 to a stronger extent than continuous CR, suggesting individualized dietary intervention.

Soluble guanylate cyclase chronic stimulation effects on cardiovascular reactivity in cafeteria diet-induced rat model of metabolic syndrome.

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 µM)) and thoracic aorta (phenylephrine (1 nM-10 µM), acetylcholine (1 nM-10 µM), and sodium nitroprusside (SNP) (0.1 nM-0.1 µM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in ß-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α1-adrenoceptor-induced vasoconstriction, and restored cardiac inotropy and coronary vasodilation. These findings suggest that BAY 41-2272 may be a potential novel drug for preventing metabolic and cardiovascular complications of metabolic syndrome.

Application of ELISA Technique and Human Microsomes in the Search for 11ß-Hydroxysteroid Dehydrogenase Inhibitors.

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.

Associations between Fatty Acid Intake and Status, Desaturase Activities, and FADS Gene Polymorphism in Centrally Obese Postmenopausal Polish Women.

Fatty acid (FA) status is associated with the risk of several diet-related diseases. Since postmenopausal women are at increased risk of cardiometabolic disturbances, determinants of FA metabolism should be fully understood in this group. We hypothesize that FA metabolism in postmenopausal Polish women may depend on current macronutrient intake and on fatty acid desaturase (FADS) gene polymorphism. One-hundred-and-twenty-eight postmenopausal women with central obesity were recruited to the study and their dietary intake, FA composition in red blood cells (RBC), and rs174556, rs174561, rs174547, and rs3834458 polymorphism of the FADS gene were analyzed. Higher levels of 18:2n-6t level in RBC were associated with higher protein or fat intake or with lower carbohydrate intake. The minor allele carriers of rs174561 of the fatty acid desaturase 1 (FADS1) gene had 9.7% lower concentration of 20:4n⁻6 in RBC (p < 0.05), but there were no other associations between other FA in RBC levels and FADS1 or fatty acid desaturase 2 (FADS2) polymorphisms. The mean D5D value was 15.3⁻17.9% lower in the minor allele carriers of each SNPs. We concluded that protein and carbohydrate intake may be associated with FA concentrations in RBC in centrally obese postmenopausal Polish women. The D5D value may be affected by FADS1 or FADS2 polymorphism.

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze α,ß-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.

[THE MODE OF EVALUATION OF FUNCTIONAL ACTIVITY OF C3-CONVERTASE OF CLASSIC PATH OF ACTIVATION OF COMPLEMENT].

The technique of detection of stabilization of C3-convertase classical way of activation of system of complement inhuman blood serum. The technique comprises two stages and is based on applying a reaction of lysis of erythrocytes of sheep sensitized by antibodies using 0.8% human blood serum. Preliminary an incubation of two samples (experimental and control) is applied during 10 min. and then reaction of activation of complement is stopped by adding a buffer containing 10 mM of EDTA. In control sample degree of lysis of erythrocytes is established and experimental sample is additionally incubated during 30 min at 37oC and then degree of lysis is determined. The activity of C3-convertase is calculated as a difference between degree of lysis and in experimental and control samples. The difference more than 10% is considered as a pathological state conditioned by stabilization of C3-convertase of classical way of activation of system of complement. The studies were carried out concerning stabilization of C3-convertase of classical way of activation of compliment in 31 patients with abdominal obesity. It is demonstrated that in 87% of patients with abdominal obesity stabilization of C3-convertase was established.

Increased glycogen synthase kinase-3ß and hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to glucocorticoid-induced mouse visceral adiposity.

BACKGROUND: Increased adiposity in visceral depots is a crucial feature associated with glucocorticoid (GC) excess. The action of GCs in a target tissue is regulated by GC receptor (GR) and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6pdh). Glycogen synthase kinase-3ß (GSK3ß) is known to be a crucial mediator of ligand-dependent gene transcription. We hypothesized that the major effects of corticosteroids on adipose fat accumulation are in part mediated by changes in GSK3ß and H6pdh. METHODS: We characterized the alterations of GSK3ß and GC metabolic enzymes, and determined the impact of GR antagonist mifepristone on obesity-related genes and the expression of H6pdh and 11ß-HSD1 in adipose tissue of mice exposed to excess GC as well as in in vitro studies using 3T3-L1 adipocytes treated with GCs. RESULTS: Corticosterone (CORT) exposure increased abdominal fat mass and induced expression of lipid synthase acetyl-CoA carboxylase and ATP-citrate lyase with activation of GSK3ß phosphorylation in abdominal adipose tissue of C57BL/6J mice. Increased pSer(9) GSK3ß was correlated with the induction of H6pdh and 11ß-HSD1. In addition, mifepristone treatment reversed the production of H6pdh and attenuated CORT-mediated production of 11ß-HSD1 and lipogenic gene expression with reduction of pSer(9) GSK3ß, thereby leading to improvement of phenotype of adiposity within adipose tissue in mice treated with excess GCs. Suppression of pSer(9) GSK3ß by mifepristone was accompanied by activation of pThr(308) Akt and blockade of CORT-induced adipogenic transcriptor C/EBPα and PPARγ. In addition, mifepristone also attenuated CORT-mediated activation of IRE1α/XBP1. In addition, reduction of H6pdh by shRNA showed comparable effects to mifepristone on attenuating CORT-induced expression of GC metabolic enzymes and improved lipid accumulation in vitro in 3T3-L1 adipocytes. CONCLUSION: These findings suggest that elevated adipose GSK3ß and H6pdh expression contribute to 11ß-HSD1 mediating hypercortisolism associated with visceral adiposity.

Biliverdin reductase isozymes in metabolism.

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets.

PCSK9 levels in abdominally obese men: association with cardiometabolic risk profile and effects of a one-year lifestyle modification program.

OBJECTIVES: Studies performed in rodents have suggested a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in insulin resistance and impaired body fat distribution. Our objective was to examine the relationships between markers of adiposity and insulin resistance and plasma PCSK9 levels in humans. In addition, we explored the effect of a one-year lifestyle modification program on plasma PCSK9 levels in abdominally obese, dyslipidemic men. METHODS: Plasma PCSK9 levels were measured by ELISA in 175 abdominally obese, dyslipidemic sedentary men. Of these abdominally obese men, 117 non-diabetic individuals completed a one-year lifestyle modification program aiming at increasing cardiorespiratory fitness levels and improving nutritional quality. RESULTS: We found no association between plasma PCSK9 levels and body mass index, waist circumference, fat and fat-free mass, or visceral and subcutaneous adipose tissue measured by computed tomography. Compared to men with the lowest PCSK9 levels (bottom tertile), those with the highest PCSK9 levels (top tertile) had the most detrimental lipoprotein-lipid profile including lower LDL particle size (253.6 ± 4.0 vs. 251.6 ± 4.0 Å, p < 0.05) and higher apolipoprotein C-III levels (36.8 ± 10.6 vs. 32.3 ± 32.3, p < 0.05). These men were also characterized by higher HOMA-IR indices (6.78 ± 3.01 vs. 5.54 ± 2.91, p < 0.05). After one year, study participants lost on average 6.7 ± 4.6 kg (p < 0.0001). Plasma PCSK9 decreased by 9.2 ± 53.7 ng/ml (3.8%, p = 0.07). CONCLUSIONS: Plasma PCSK9 levels are not associated with body fat distribution indices, modestly associated with markers of insulin resistance and LDL particle size and are slightly affected by a lifestyle modification program in abdominally obese men.

Adipose tissue diacylglycerol acyltransferase activity and blood lipoprotein triglyceride enrichment in women with abdominal obesity.

UNLABELLED: Previous studies have suggested altered triglyceride (TG) storage in patients with abdominal obesity and blood lipid disorders. OBJECTIVE: We hypothesized that women with abdominal obesity and a dysmetabolic profile have low DGAT activity in their abdominal fat compartments. METHODS: Paired omental (OM) and subcutaneous (SC) adipose tissue samples were obtained surgically from 39 women undergoing abdominal hysterectomies. Body composition and fat distribution were measured by dual energy x-ray absorptiometry and computed tomography. DGAT activity was measured by acylation of sn-l,2-diacylglycerol with [(14)C] oleoyl-CoA in microsomal fractions isolated from whole adipose tissue homogenates. DGAT activity was calculated on the basis of picomoles (pmol) TG synthesized in the assay per min per mg lipid, per µg protein or per 1000 cells. RESULTS: No depot differences were found when DGAT activity was reported per µg microsomal protein or per 1000 cells. DGAT activity in either depot was not associated with adipocyte diameters and blood lipid profile variables. DGAT activity per mg lipid was higher in OM than in abdominal SC adipose tissue (0.43 ± 0.20 vs. 0.34 ± 0.18 pmol/min/mg lipid, p < 0.05). OM DGAT activity was negatively correlated with OM adipocyte diameter and visceral adipose tissue area (r = -0.43, p < 0.01 and r = -0.38, p < 0.05 respectively). Plasma total, LDL and HDL TG levels were negatively associated with OM DGAT activity independent of total body fat mass (r = -0.39, p < 0.05, r = -0.46, p < 0.001 and r = -0.40, p < 0.05 respectively). CONCLUSION: A defect in adipose tissue DGAT activity is predictive of adiposity and blood lipoprotein TG enrichment only when considering activity per tissue lipid mass.

Effects of glucomannan-enriched, aronia juice-based supplement on cellular antioxidant enzymes and membrane lipid status in subjects with abdominal obesity.

The aim of this study was to analyze the effects of a 4-week-long consumption of glucomannan-enriched, aronia juice-based supplement on anthropometric parameters, membrane fatty acid profile, and status of antioxidant enzymes in erythrocytes obtained from postmenopausal women with abdominal obesity. Twenty women aged 45-65 with a mean body mass index (BMI) of 36.1 ± 4.4 kg/m(2) and waist circumference of 104.8 ± 10.1 cm were enrolled. Participants were instructed to consume 100 mL of supplement per day as part of their regular diet. A significant increase in the content of n-3 (P < 0.05) polyunsaturated fatty acids in membrane phospholipids was observed, with a marked increase in the level of docosahexaenoic fatty acid (P < 0.05). Accordingly, a decrease in the n-6 and n-3 fatty acids ratio was observed (P < 0.05). The observed effects were accompanied with an increase in glutathione peroxidase activity (P < 0.05). Values for BMI (P < 0.001), waist circumference (P < 0.001), and systolic blood pressure (P < 0.05) were significantly lower after the intervention. The obtained results indicate a positive impact of tested supplement on cellular oxidative damage, blood pressure, and anthropometric indices of obesity.

Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults.

Although obesity is a key predisposing risk factor in the development of insulin resistance (IR) and type 2 diabetes mellitus, not all obese individuals develop IR. This study aimed to identify key anthropometric and biochemical parameters that predict insulin sensitivity in overweight and obese adults. Based on previous literature, we hypothesized that markers of insulin sensitivity would be negatively correlated with plasma concentrations of free fatty acids and liver enzymes. Forty nondiabetic adult participants (body mass index ≥ 25.0 kg/m²) were recruited. Data collection included anthropometric measurements and fasting plasma samples for the quantification of liver enzymes (alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase), blood lipid profile, and markers of insulin sensitivity. Questionnaires relating to dietary intake, physical activity, and fatigue were also completed. Insulin and Homeostasis Model of Assessment (HOMA) scores were significantly correlated with indirect measures of central obesity (P < .05). Glycosylated hemoglobin, insulin, and HOMA scores for IR were all positively correlated with selected liver function markers (P < .05). Scores of HOMA-IR were significantly positively correlated with plasma phospholipid levels of n-3 fatty acids (P = .04) and ratio of n-3/n-6 fatty acids (P < .05) and negatively correlated with n-6 fatty acids (P = .03). No significant correlations were found between markers of insulin sensitivity and cholesterol levels, physical activity, or self-reported fatigue. These results have reinforced the integral role of liver function in the development of IR. Despite previous data linking elevations in free fatty acid to the development of IR, we found no relationship between these variables in this study.

Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome.

Ca(+) mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) has been associated with the development of left ventricular diastolic dysfunction in insulin-resistant cardiomyopathy. However, the molecular causes underlying SERCA2a alterations induced by insulin resistance and related metabolic disorders, such as metabolic syndrome (MetS), are not completely understood. In this study, we used a sucrose-fed rat model of MetS to test the hypothesis that decreased SERCA2a activity is mediated by elevated oxidative stress produced in the MetS heart. Production of ROS and cytosolic Ca(2+) concentration were recorded in left ventricular myocytes using confocal imaging. The level of SERCA2a oxidation was determined in left ventricular homogenates by biotinylated iodoacetamide labeling. Compared with control rats, sucrose-fed rats exhibited several characteristics of MetS, including central obesity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Moreover, relative to myocytes from control rats, myocytes from MetS rats exhibited elevated basal production of ROS accompanied by slowed cytosolic Ca(2+) removal, reflected by prolonged Ca(2+) transients. The slowed cytosolic Ca(2+) removal was associated with a significant decrease in SERCA2a-mediated Ca(2+) reuptake and increased SERCA2a oxidation. Importantly, myocytes from MetS rats treated with the antioxidant N-acetylcysteine showed normal ROS levels and SERCA2a-mediated Ca(2+) reuptake as well as accelerated cytosolic Ca(2+) removal. These data suggest that elevated oxidative stress may induce oxidative modifications on SERCA2a leading to abnormal function of this protein in the MetS heart.

Breakfast frequency and development of metabolic risk.

OBJECTIVE: The relation of breakfast intake frequency to metabolic health is not well studied. The aim of this study was to examine breakfast intake frequency with incidence of metabolic conditions. RESEARCH DESIGN AND METHODS: We performed an analysis of 3,598 participants from the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of diabetes in the year 7 examination when breakfast and dietary habits were assessed (1992-1993) and participated in at least one of the five subsequent follow-up examinations over 18 years. RESULTS: Relative to those with infrequent breakfast consumption (0-3 days/week), participants who reported eating breakfast daily gained 1.9 kg less weight over 18 years (P=0.001). In a Cox regression analysis, there was a stepwise decrease in risk across conditions in frequent breakfast consumers (4-6 days/week) and daily consumers. The results for incidence of abdominal obesity, obesity, metabolic syndrome, and hypertension remained significant after adjustment for baseline measures of adiposity (waist circumference or BMI) in daily breakfast consumers. Hazard ratios (HRs) and 95% CIs for daily breakfast consumption were as follows: abdominal obesity HR 0.78 (95% CI 0.66-0.91), obesity 0.80 (0.67-0.96), metabolic syndrome 0.82 (0.69-0.98), and hypertension 0.84 (0.72-0.99). For type 2 diabetes, the corresponding estimate was 0.81 (0.63-1.05), with a significant stepwise inverse association in black men and white men and women but no association in black women. There was no evidence of differential results for high versus low overall dietary quality. CONCLUSIONS: Daily breakfast intake is strongly associated with reduced risk of a spectrum of metabolic conditions.

Abdominal adiposity is associated with fatty acid desaturase activity in boys: implications for C-reactive protein and insulin resistance.

Fatty acid composition, which is altered in patients with abdominal obesity, is influenced not only by dietary intake but also by the desaturating enzymes stearoyl-CoA desaturase (SCD), delta-6 desaturase (D6D) and delta-5 desaturase (D5D). We investigated desaturase activities and their associations with metabolic risk factors, C-reactive protein levels (CRP) and insulin resistance in Japanese children. There were 237 school children in this study; 115 were boys. The fatty acid composition of plasma phospholipids was analyzed, and the following desaturase activities were estimated: SCD (16:1n-7/16:0 and 18:1n-9/18:0), D6D (20:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6). D6D and D5D activities, but not SCD activity, were significantly associated with triglyceride levels, high-density lipoprotein cholesterol levels and insulin resistance in both sexes, and with CRP levels in boys. In addition, increased abdominal adiposity was significantly associated with increased D6D activity, and decreased D5D activity and insulin resistance in both sexes, and with increased CRP levels in boys. The n-6 polyunsaturated fatty acid desaturation pathway may be associated with metabolic risk factors, insulin resistance and increased inflammation in children with abdominal obesity, especially in boys.

Serum alkaline phosphatase, body composition, and risk of metabolic syndrome in middle-aged Korean.

Some papers have suggested that alkaline phosphatase (ALP) level is a predictor of the metabolic syndrome (MetS) in the general population. However, the association is still controversial, and the mechanisms underlying an association between ALP level and the MetS have not been elucidated. We analyzed the association between serum ALP level and the development of the MetS over a 4-year period. A total of 14,224 subjects who visited the Health Promotion Center for a medical examination in 2005 were followed up after 4 years. Serum ALP level correlated positively with body fat mass and visceral fat mass. The adjusted geometric mean ALP levels were higher in subjects with elevated C-reactive protein level or greater fat mass (P < 0.001). None of the subjects had the MetS at baseline, but 1,179 exhibited the MetS at the 4-year follow-up. After multiple adjustments, the odds ratio (OR) was substantially higher for development of the MetS (OR 1.56, 95% confidence intervals, 1.21-2.01) in subjects in the highest ALP quintile compared with those in the lowest quintile. After adjusting for various covariates, we found significant associations between the quintile of serum ALP level and abdominal obesity, low high-density lipoprotein cholesterol level, and high triglyceride level. Higher serum ALP level was a significant predictor of the MetS in middle-aged Koreans. Serum ALP level correlated positively with body fat mass and independently with a more atherogenic lipid profile in the general population in Korea.

MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation.

Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients.

Baicalein, a natural product, selectively activating AMPKα(2) and ameliorates metabolic disorder in diet-induced mice.

The aim of the present study was to determine the effect of baicalein on metabolic syndrome induced by a high-fat diet in mice. The mice developed obesity, dyslipidemia, fatty liver, diabetes and insulin resistance. These disorders were effectively normalized in baicalein-treated mice. Further investigation revealed that the inhibitory effect on inflammation and insulin resistance was mediated by inhibition of the MAPKs pathway and activation of the IRS1/PI3K/Akt pathway. The lipid-lowering effect was attributed to the blocking of synthesis way mediated by SERBP-1c, PPARγ and the increased fatty acid oxidation. All of these effects depended on AMPKα activation. These results were confirmed in the primary hepatocytes from wild type and AMPKα(2)(-/-) mice. However, the IRS-1/PI3K/AKT pathway showed no change, which may be due to the time of stimulation and concentration. Thus, these data suggested that baicalein protects mice from metabolic syndrome through an AMPKα(2)-dependent mechanism involving multiple intracellular signaling pathways.

Skeletal muscle 11ßHSD1 activity of nondiabetic subjects is unaltered in central obesity-associated insulin resistance.

Local activation of glucocorticoids in insulin target tissues by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) has been implicated in the etiology of the metabolic syndrome. In obesity, adipose tissue 11ßHSD1 is upregulated, leading to the generation of higher tissue levels of cortisol, which may increase insulin resistance. However, skeletal muscle is the predominant site of insulin-mediated glucose disposal, which is known to be reduced in obesity. We aimed to determine if there is any relationship between skeletal muscle 11ßHSD1 and markers of central adiposity and insulin resistance in nondiabetic subjects. 20 nondiabetic volunteers (8 males and 12 females, mean age 55 ± 13 years, body mass index 21.5-47.6, mean 30.4 ± 1.6 kg/m (2)) underwent a single fasting blood sample followed by a muscle biopsy of vastus lateralis under local anesthetic. Fasting glucose, insulin and adiponectin were measured in serum. Skeletal muscle 11ßHSD1 oxoreductase activity was determined by measuring the conversion of radiolabelled (3)H-cortisone to cortisol by thin layer chromatography. When subjects were categorised according to abdominal obesity (waist circumference ≥ 102 cm in men, ≥ 88 cm in women), there was no difference between the groups in skeletal muscle 11ßHSD1 activity. There was no correlation between body mass index or waist circumference and 11ßHSD1 activity or between HOMA and 11ßHSD1 activity. Skeletal muscle 11ßHSD1 oxoreductase activity is not altered in nondiabetic subjects with central obesity-associated insulin resistance. It is therefore unlikely that the in vivo insulin resistance observed in skeletal muscle of centrally obese subjects is mediated by alterations in 11ßHSD1.