Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins.

BACKGROUND: Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. METHODS: Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety. RESULTS: Firibastat lowered systolic AOBP by 9.5 mm Hg ( P<0.0001) and diastolic AOBP by 4.2 mm Hg ( P<0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg ( P<0.0001) in obese patients, by 10.5 mm Hg ( P<0.0001) in blacks, and 8.9 mm Hg ( P<0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed. CONCLUSIONS: Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.

Body mass index is independently associated with xanthine oxidase activity in overweight/obese population.

PURPOSE: The pathophysiological mechanism of the relationship between xanthine oxidase (XO) activity and obesity has not been completely elucidated. Since inflammation and oxidative stress are regarded as key determinants of enlarged adipose tissue, we aimed to investigate the association between oxidative stress (as measured with XO activity), inflammation [as measured with high-sensitivity C-reactive protein (hsCRP)] and obesity [as measured with body mass index (BMI)]. In addition, we wanted to examine whether hsCRP itself plays an independent role in XO activity increase or it is only mediated through obesity. METHODS: A total of 118 overweight/obese volunteers (mean age 54.76 ± 15.13 years) were included in the current cross-sectional study. Anthropometric, biochemical parameters, and blood pressure were obtained. RESULTS: Significant differences between age, BMI, waist circumference, concentrations of uric acid and hsCRP, as well as xanthine dehydrogenase (XDH) activities were evident among XO tertile groups. Multiple linear regression analysis revealed that BMI (beta = 0.241, p = 0.012) and XDH (beta = - 0.489, p < 0.001) are the independent predictors of XO activity (R2-adjusted = 0.333), whereas hsCRP lost its independent role in XO activity prediction. CONCLUSION: Obesity (as determined with increased BMI) is an independent predictor of high XO activity in overweight/obese population. LEVEL OF EVIDENCE: Level V: cross-sectional descriptive study.

Predictors of obesity and overweight in preschoolers: The role of parenting styles and feeding practices.

Childhood obesity/overweight (OB/OW) displayed a rapid increase and high prevalence in the last few decades in preschool-aged children, which raised health concerns across the world and motivated researchers to investigate the factors that underlie childhood obesity. The current study examined parenting styles and child-feeding practices as potential predictors for OB/OW in preschool children, controlling for child's temperament, which has been shown to be linked with OB/OW. The sample included 61 normal weight (NW) and 61 obese/overweight (OB/OW) Turkish pre-schoolers (M age = 62.2 months; SD = 7.64, range = 45-80 months). Parenting styles (authoritarian, authoritative), child-feeding practices (restriction, pressure to eat, monitoring), and child's temperament (negative affectivity) were measured with mothers' reports. Results showed that authoritarian parenting and maternal pressure to eat were the two parenting variables that significantly predicted child's weight status; the odds of being OB/OW was 4.71 times higher in children whose mothers used higher authoritarian parenting style, and was 0.44 times lower when mothers pressured their child to eat. These findings suggest that understanding the unique role of different aspects of parenting in the risk of early OB/OW status of children would be important in developing more effective interventions from early years in life.

Opposite effects of a glucokinase activator and metformin on glucose-regulated gene expression in hepatocytes.

AIM: Small molecule activators of glucokinase (GKAs) have been explored extensively as potential anti-hyperglycaemic drugs for type 2 diabetes (T2D). Several GKAs were remarkably effective in lowering blood glucose during early therapy but then lost their glycaemic efficacy chronically during clinical trials. MATERIALS AND METHODS: We used rat hepatocytes to test the hypothesis that GKAs raise hepatocyte glucose 6-phosphate (G6P, the glucokinase product) and down-stream metabolites with consequent repression of the liver glucokinase gene ( Gck). We compared a GKA with metformin, the most widely prescribed drug for T2D. RESULTS: Treatment of hepatocytes with 25 mM glucose raised cell G6P, concomitantly with Gck repression and induction of G6pc (glucose 6-phosphatase) and Pklr (pyruvate kinase). A GKA mimicked high glucose by raising G6P and fructose-2,6-bisphosphate, a regulatory metabolite, causing a left-shift in glucose responsiveness on gene regulation. Fructose, like the GKA, repressed Gck but modestly induced G6pc. 2-Deoxyglucose, which is phosphorylated by glucokinase but not further metabolized caused Gck repression but not G6pc induction, implicating the glucokinase product in Gck repression. Metformin counteracted the effect of high glucose on the elevated G6P and fructose 2,6-bisphosphate and on Gck repression, recruitment of Mlx-ChREBP to the G6pc and Pklr promoters and induction of these genes. CONCLUSIONS: Elevation in hepatocyte G6P and downstream metabolites, with consequent liver Gck repression, is a potential contributing mechanism to the loss of GKA efficacy during chronic therapy. Cell metformin loads within the therapeutic range attenuate the effect of high glucose on G6P and on glucose-regulated gene expression.

Correlations of Complete Blood Count with Alanine and Aspartate Transaminase in Chinese Subjects and Prediction Based on Back-Propagation Artificial Neural Network (BP-ANN).

BACKGROUND The complete blood count (CBC) is the most common examination used to monitor overall health in clinical practice. Whether there is a relationship between CBC indexes and alanine transaminase (ALT) and aspartate aminotransferase (AST) has been unclear. MATERIAL AND METHODS In this study, 572 normal-weight and 346 overweight Chinese subjects were recruited. The relationship between CBC indexes with ALT and AST were analyzed by Pearson and Spearman correlations according to their sex, then we conducted colinearity diagnostics and multiple linear regression (MLR) analysis. A prediction model was developed by a back-propagation artificial neural network (BP-ANN). RESULTS ALT was related to 4 CBC indexes in the male normal-weight group and 3 CBC indexes in the female group. In the overweight group, ALT had a similar relationship with the normal group, but there was only 1 index related with AST in the normal-weight group and male overweight groups. The ALT regression models were developed in normal-weight and overweight people, which had better correlation coefficient (R>0.3). After training 1000 epochs, the BP-ANN models of ALT achieved higher correlations than MLR models in normal-weight and overweight people. CONCLUSIONS ALT is a more suitable index than AST for developing a regression model. ALT can be predicted by CBC indexes in normal-weight and overweight individuals based on a BP-ANN model, which was better than MLR analysis.

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia.

BACKGROUND: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. PATIENTS AND METHODS: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. RESULTS: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. CONCLUSIONS: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Association between PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), GCKR (rs780094), and elevated transaminase levels in overweight/obese Mexican adults.

There is scarce information about the link between specific single-nucleotide polymorphisms (SNPs) and risk of liver disease among Latinos, despite the disproportionate burden of disease among this population. Our aim was to investigate nine SNPs in or near the following genes: PNPLA3, LYPLAL1, PPP1R3B, GCKR, NCAN, IRS1, PPARG, and ADIPOR2 and examine their association with persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels in Mexican adults. Data and samples were collected from 741 participants in the Mexican Health Worker Cohort Study, in Cuernavaca, Mexico. We identified 207 cases who had persistently elevated levels of ALT or AST (≥40 U/L) and 534 controls with at least two consecutive normal ALT or AST results in a 6 month period, during 2004-2006 and 2011-2013. TaqMan assays were used to genotype the SNPs. The risk allele of PNPLA3 rs738409 was found to be associated with persistently elevated levels of ALT or AST, adjusting for age, sex, BMI, type 2 diabetes, and ancestry: (OR 2.28, 95 % CI 1.13, 4.58). A significant association was found between the LYPLAL1, PPP1R3B, and GCKR risk alleles and elevated ALT or AST levels among overweight/obese adults. These results suggest that among Mexicans, the PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) polymorphisms may be associated with a greater risk of chronic liver disease among overweight adults. This study is the first to examine these nine SNPs in a sample of adults in Mexico.

Role of SN1 lipases on plasma lipids in metabolic syndrome and obesity.

OBJECTIVE: To assess the phospholipase activity of endothelial (EL) and hepatic lipase (HL) in postheparin plasma of subjects with metabolic syndrome (MS)/obesity and their relationship with atherogenic and antiatherogenic lipoproteins. Additionally, to evaluate lipoprotein lipase (LPL) and HL activity as triglyceride (TG)-hydrolyses to complete the analyses of SN1 lipolytic enzymes in the same patient. APPROACH AND RESULTS: Plasma EL, HL, and LPL activities were evaluated in 59 patients with MS and 36 controls. A trend toward higher EL activity was observed in MS. EL activity was increased in obese compared with normal weight group (P=0.009) and was negatively associated with high-density lipoprotein-cholesterol (P=0.014 and P=0.005) and apolipoprotein A-I (P=0.045 and P=0.001) in control and MS group, respectively. HL activity, as TG-hydrolase, was increased in MS (P=0.025) as well as in obese group (P=0.017); directly correlated with low-density lipoprotein-cholesterol (P=0.005) and apolipoprotein B (P=0.003) and negatively with high-density lipoprotein-cholesterol (P=0.021) in control group. LPL was decreased in MS (P<0.001) as well as in overweight and obese compared with normal weight group (P=0.015 and P=0.004, respectively); inversely correlated %TG-very low-density lipoproteins (P=0.04) and TG/apolipoprotein B index (P=0.013) in control group. These associations were not found in MS. CONCLUSIONS: We describe for the first time EL and HL activity as phospholipases in MS/obesity, being both responsible for high-density lipoprotein catabolism. Our results elucidate part of the remaining controversies about SN1 lipases activity in MS and different grades of obesity. The impact of insulin resistance on the activity of the 3 enzymes determines the lipoprotein alterations observed in these states.

Waist-to-height ratio is more closely associated with alanine aminotransferase levels than body mass index and waist circumference among population-based children: a cross-sectional study in Japan.

BACKGROUND: An association between anthropometric measurements, including waist circumference (WC), and alanine aminotransferase (ALT) levels has been reported among adults. However, studies conducted among population-based elementary schoolchildren to date have been limited, especially in Japan, where the measurement of WC and blood collection are not usually performed in the annual health examination at elementary schools. The present study investigated the association between anthropometric measurements and ALT levels among population-based elementary schoolchildren in Japan. METHODS: Subjects were fourth-grade schoolchildren (aged 9 or 10) from the town of Ina in Saitama Prefecture, Japan during 2004-2009. The height, weight, and WC of each subject were measured, and blood samples were drawn to measure ALT levels. Childhood overweight or obesity was defined according to the age- and sex-specific cut-off points proposed by the International Obesity Task Force. Spearman's correlation coefficients between anthropometric measurements (body mass index (BMI), WC, and waist-to-height ratio (WHtR)) and ALT levels were calculated. RESULTS: Data from 2499 subjects (1293 boys and 1206 girls) were analyzed. BMI, WC, and WHtR were significantly positively correlated with ALT levels; the correlation coefficient of ALT levels with WHtR was higher than that with BMI and WC in boys and girls. In the analysis stratified by physique (non-overweight/obesity, overweight, or obesity), all anthropometric measurements were significantly positively correlated with ALT levels among boys, while only WHtR was significantly positively correlated with ALT levels among girls. Moreover, the correlation coefficient of ALT levels with WHtR was more pronounced than that with BMI and WC in the non-overweight/obesity group, in the overweight group, and in the obesity group for each sex. CONCLUSIONS: The present study showed that WHtR was more closely associated with ALT levels than BMI and WC. Furthermore, only WHtR was significantly positively associated with ALT levels regardless of sex and physique. This study suggests that it is more useful to monitor WHtR than BMI and WC as a surrogate for ALT levels among population-based elementary schoolchildren.

Increased levels of circulating arginase I in overweight compared to normal weight adolescents.

BACKGROUND AND AIMS: Overweight and the metabolic syndrome have become major problems, especially in children and adolescents. Obesity at a young age increases the risk for cardiovascular diseases and diabetes mellitus later in life. An early event in the development of cardiovascular disease is endothelial dysfunction which is found in obese young individuals. Increased activity of the enzyme arginase has been described as a central mechanism for endothelial dysfunction, especially in patients with diabetes mellitus. The aim of the study was to determine plasma levels of arginase in overweight adolescents. METHODS: Sixty-six male German adolescents (age: 15.2 ± 1.1 years old) were included. Thirty-one of them were overweight (>90th age-specific weight percentile). Plasma arginase I and tumor necrosis factor alpha (TNFα) were determined. In addition, clinical data were recorded and anthropometrical measurements of obesity were performed. RESULTS: Overweight adolescents had a higher systolic blood pressure, lower high-density lipoprotein and increased levels of high-sensitive C-reactive protein (CRP). Circulating arginase I was elevated in overweight adolescents (95.8 ± 68.2 ng/ml) compared to normal weight adolescents (39.3 ± 26.9 ng/ml, p < 0.001) and correlated with markers of obesity. There was no difference between the two groups regarding TNFα. CONCLUSIONS: We demonstrate that arginase I levels are increased in obese adolescents. Knowing the important role for arginase in endothelial dysfunction, elevated levels of arginase I may represent a link between obesity, endothelial dysfunction and related comorbidities.

[A cross-sectional survey on prevalence and risk factors for abnormal plasma liver enzymes in overweight or obese patients with type 2 diabetes mellitus].

OBJECTIVE: To explore the prevalence and risk factors for abnormal plasma liver enzymes in patients with type 2 diabetes mellitus. METHODS: Overweight or obese patients with type 2 diabetes were recruited from 60 tertiary and secondary hospitals in Guangdong Province between August 2011 and March 2012. The abnormal plasma liver enzymes was diagnosed as alanine aminotransferase >40 U/L and/or aspartate aminotransferase >40 U/L. Binary Logistic regression was used to assess the associations between abnormal plasma liver enzymes and associated risk factors. RESULTS: The abnormal plasma liver enzymes were detected in 709/3543 diabetics with overweight or obesity. And the prevalence of abnormal plasma liver enzymes was 20.0%. According to binary Logistic regression analysis, the presence of abnormal plasma liver enzymes was associated with male gender (OR = 1.603, 95%CI: 1.247-2.061), higher HbA1c(OR = 1.049, 95%CI: 1.005-1.096), higher body mass index (OR = 1.058, 95%CI: 1.014-1.103), higher waist circumference (OR = 1.019, 95%CI: 1.006-1.032), higher triglyceride level (OR = 1.053, 95%CI: 1.008-1.100), adiposis hepatica (OR = 1.543; 95%CI: 1.244-1.914), regular exercises (OR = 0.591, 95%CI: 0.472-0.740) and diet control (OR = 0.794, 95%CI: 0.635-0.993). CONCLUSIONS: There is a high prevalence of abnormal plasma liver enzymes in overweight/obese with diabetics. And decreasing the levels of HbA1c, body mass index, waist circumference and triglycerides, regular exercises and diet control may decrease its prevalence.

Increase in MMP-2 activity in overweight and obese women is associated with menopausal status.

BACKGROUND: Metalloproteinases (MMPs) are synthesized in the subendothelium and are involved in the atherosclerosis and cardiovascular disease process because of their major significance in vascular remodeling and plaque rupture. MMPs are also synthesized in adipose tissue during angiogenesis; however, the role of these enzymes in obesity and insulin-resistant states is still controversial. OBJECTIVE: To evaluate MMP-2 activity in the circulation of overweight and obese women and in normal-weight controls, and to associate the levels of these factors with metabolic, adipose tissue and inflammation biomarkers. METHODS: Plasma MMP-2 activity, adiponectin and C-reactive protein concentration, lipoprotein profile and HOMA were determined in 39 healthy women (13 normal weight and 26 overweight/obese). RESULTS: Overweight/obese women were older (p < 0.001) than normal-weight women; 20/26 of overweight/obese women were postmenopausal compared with 4/13 of normal-weight women. Overweight/obese women had significantly higher plasma activity of MMP-2 than controls (mean relative area: 0.81 (range 0.4-1.92) vs. 1.33 (range 0.4-3.1); p < 0.005); this difference was lost after adjusting for menopausal status. MMP-2 activity positively correlated with waist circumference (p < 0.002), HOMA (p < 0.003), and high-sensitivity C-reactive protein (p < 0.05), apolipoprotein B (p = 0.006) and triglyceride/high density lipoprotein (HDL) cholesterol index (p < 0.001), and negatively with HDL cholesterol (p < 0.001), HDL2 cholesterol (p < 0.008), HDL3 cholesterol (p < 0.05) and adiponectin (p < 0.05). The association with HOMA and adiponectin persisted even after adjusting for menopausal status. CONCLUSION: Our finding of increased plasma activity of MMP-2 in overweight/obese women, associated with menopausal status, is important given that it fits in with an early stage of cardiovascular disease; the association of MMP-2 activity with obesity markers may be a link between adipose tissue and risk for cardiovascular disease.

Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT.

While the benefits of exercise are clear, many unresolved issues surround the optimal exercise prescription. Many organizations recommend aerobic training (AT) and resistance training (RT), yet few studies have compared their effects alone or in combination. The purpose of this study, part of Studies Targeting Risk Reduction Interventions Through Defined Exercise-Aerobic Training and/or Resistance Training (STRRIDE/AT/RT), was to compare the effects of AT, RT, and the full combination (AT/RT) on central ectopic fat, liver enzymes, and fasting insulin resistance [homeostatic model assessment (HOMA)]. In a randomized trial, 249 subjects [18-70 yr old, overweight, sedentary, with moderate dyslipidemia (LDL cholesterol 130-190 mg/dl or HDL cholesterol ≤ 40 mg/dl for men or ≤ 45 mg/dl for women)] performed an initial 4-mo run-in period. Of these, 196 finished the run-in and were randomized into one of the following 8-mo exercise-training groups: 1) RT, which comprised 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set, 2) AT, which was equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O(2) uptake, and 3) full AT + full RT (AT/RT), with 155 subjects completing the intervention. The primary outcome variables were as follows: visceral and liver fat via CT, plasma liver enzymes, and HOMA. AT led to significant reductions in liver fat, visceral fat, alanine aminotransferase, HOMA, and total and subcutaneous abdominal fat (all P < 0.05). RT resulted in a decrease in subcutaneous abdominal fat (P < 0.05) but did not significantly improve the other variables. AT was more effective than RT at improving visceral fat, liver-to-spleen ratio, and total abdominal fat (all P < 0.05) and trended toward a greater reduction in liver fat score (P < 0.10). The effects of AT/RT were statistically indistinguishable from the effects of AT. These data show that, for overweight and obese individuals who want to reduce measures of visceral fat and fatty liver infiltration and improve HOMA and alanine aminotransferase, a moderate amount of aerobic exercise is the most time-efficient and effective exercise mode.

[Relationship between alanine aminotransferase and overweight or obesity in children].

OBJECTIVE: To study the association of alanine aminotransferase (ALT) with overweight or obesity in children. METHODS: A total of 2889 healthy children and 702 overweight or obese children aged from 7 to 18 years who had received a physical examination were enrolled. Height, body weight, waist circumference, and blood pressure were measured, and the biochemical indicators including blood glucose, blood lipids, ALT, and insulin were detected. The insulin resistance index were calculated. RESULTS: The ALT level was significantly higher in boys than in girls. Along with the increase of BMI, the ALT level increased in the normal, overweight, and obese groups in both boys and girls. ALT was correlated with BMI, waist circumference, triglyceride, and insulin resistance index. Among the overweight or obese children, the boys with the increased ALT level had higher BMI, waist circumference, blood pressure, triglyceride, low density lipoprotein and insulin resistance index than the boys with normal ALT level (P<0.05); the girls with the increased ALT level had higher waist circumference, blood pressure and insulin resistance index and lower high density lipoprotein than the girls with normal ALT level (P<0.05). CONCLUSIONS: ALT is correlated with overweight and obesity and metabolic disorders caused by overweight and obesity such as dyslipidemia and insulin resistance.

Visceral adipose tissue and inflammation correlate with elevated liver tests in a cohort of overweight and obese patients.

OBJECTIVE: To study the relationship between elevated liver tests and high sensitive C-reactive protein (hs-CRP), as potential markers of liver inflammation and non-alcoholic steatohepatitis (NASH), with anthropometric and laboratory parameters in overweight patients, especially the relationship with visceral adipose tissue (VAT). METHODS: Patients presenting to the obesity clinic were prospectively included. Detailed anthropometry, computed tomography (CT)-measured VAT, liver tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)) and hs-CRP were assessed, along with an extended series of biochemical parameters. RESULTS: All 480 patients (gender distribution male (M)/female (F) (10/90%)) with complete data were included. Mean age was 39+/-13 years, mean BMI 34.5+/-6.0 kg m(-2). In 37.3% of the patients one or more of the liver tests were elevated. VAT was positively related to AST (r=0.18, P<0.001), ALT (r=0.29, P<0.001), ALP (r=0.16, P<0.01) and GGT (r=0.39, P<0.001). Comparing subjects with high (VAT>or=113 cm(2)) vs low (VAT<113 cm(2)) VAT levels, significant differences were noted for AST (26+/-12 vs 24+/-12 U l(-1), P=0.003), ALT (37+/-21 vs 31+/-21 U l(-1), P<0.001), ALP (76+/-20 vs 71+/-18 U l(-1), P=0.008), GGT (33+/-20 vs 25+/-15 U l(-1), P<0.001) and hs-CRP (0.62+/-0.43 vs 0.52+/-0.48 mg dl(-1), P<0.001). After correction for BMI the difference in AST and ALP between the high vs low VAT group disappeared. The differences for ALT and GGT remained significant (P=0.008 and P<0.001 respectively). After correction for hs-CRP the four different liver tests remained significantly higher in the high VAT group. A stepwise multiple regression analysis revealed that every single liver test has his own most important determinant; VAT and hs-CRP for AST, insulin resistance calculated with homeostasis model assessment (HOMA-IR) and hs-CRP for ALT and ALP, and triglycerides and VAT for GGT. CONCLUSION: In overweight and obese patients, liver tests, especially ALT and GGT, are associated with visceral fat mass. After correction for BMI and hs-CRP, ALT and GGT are significantly higher in patients with increased VAT, thereby supporting evidence for a potential key role of VAT in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

The effect of overweight and obesity on proliferation and activation of AKT and ERK in human endometria.

OBJECTIVE: To examine whether overweight and obesity could lead to increased endometrial proliferation and activation of AKT and ERK1,2 in cycling premenopausal women. METHODS: Endometrial and blood samples were obtained from women with normal endometrial histology, and allocated into three groups-normal-weight, overweight and obese-according to the subject's body mass index (BMI). Samples from obese patients with type-I endometrial cancer (EC) were included as a control. Cell proliferation was measured by immunohistochemical detection of Ki67 and phosphorylated histone H3 (p-H3). AKT and ERK1,2 activation was assessed by Western blot. Circulating steroids, leptin and insulin were measured by immunoassays. RESULTS: In endometrial samples with normal histology, epithelial cell proliferation was higher in the overweight and obese groups versus the normal-weight set (P<0.05). Proliferation indexes were positively correlated with the subject's BMI and serum levels of estrogen, leptin and insulin (P<0.05). Increased phosphorylated AKT (pAKT) (1.6-fold) and ERK1,2 (pERK1,2) (8.7-fold) were observed in endometria from obese with respect to normal-weight subjects (P<0.05). Similarly, increased phosphorylation of AKT (0.7-fold) and ERK1,2 (2.3-fold) was detected in endometria from overweight as compared with the normal-weight group (P<0.05). In women with EC, we found a significant increase in endometrial proliferation, and in pAKT and pERK1,2 expression levels when compared to patients with normal endometrial histology. CONCLUSION: These results show correlation between obesity (and overweight) and increased endometrial cell proliferation, and the activation of AKT and ERK1,2. These features could be related with the higher risk to develop type-I EC in overweight and obese women.

Pretreatment Prevotella-to-Bacteroides ratio and salivary amylase gene copy number as prognostic markers for dietary weight loss.

BACKGROUND: The inconsistent link observed between salivary amylase gene copy number (AMY1 CN) and weight management is likely modified by diet and microbiome. OBJECTIVE: Based on analysis of a previously published study, we investigated the hypothesis that interaction between diet, Prevotella-to-Bacteriodes ratio (P/B ratio), and AMY1 CN influence weight change. METHODS: Sixty-two people with increased waist circumference were randomly assigned to receive an ad libitum New Nordic Diet (NND) high in dietary fiber, whole grain, intrinsic sugars, and starch or an Average Danish (Western) Diet (ADD) for 26 weeks. All foods were provided free of charge. Before subjects were randomly assigned to receive the NND or ADD diet, blood and fecal samples were collected, from which AMY1 CN and P/B ratio, respectively, were determined. Body weight change was described by using linear mixed models, including biomarker [log10(P/B ratio) and/or AMY1 CN] diet-group interactions. RESULTS: Baseline means ± SDs of log10(P/B ratio) and AMY1 CN were -2.1 ± 1.8 and 6.6 ± 2.4, respectively. Baseline P/B ratio predicted a 0.99-kg/unit (95% CI: 0.40, 1.57; n = 54; P < 0.001) higher weight loss for those subjects on the NND compared with those on the ADD diet, whereas AMY1 CN was not found to predict weight loss differences between the NND and ADD groups [0.05 kg/CN (95% CI: -0.40, 0.51; n = 54; P = 0.83)]. However, among subjects with low AMY1 CN (<6.5 copies), baseline P/B ratio predicted a 2.12-kg/unit (95% CI: 1.37, 2.88; n = 30; P < 0.001) higher weight loss for the NND group than the ADD group. No such differences in weight loss were found among subjects in both groups with high AMY1 CN [-0.17 kg/unit (95% CI: -1.01, 0.66; n = 24; P = 0.68)]. CONCLUSIONS: The combined use of low AMY1 CN and pretreatment P/B ratio for weight loss prediction led to highly individualized weight loss results with the introduction of more fiber, whole grain, intrinsic sugars, and starch in the diet. These preliminary observations suggest that more undigested starch reaches the colon in individuals with low AMY1 CN, and that the fate of this starch depends on the gut microbiota composition. This trial was registered at clinicaltrials.gov as NCT01195610.

ACE I/D genotype, adiposity, and blood pressure in children.

BACKGROUND: Angiotensin converting enzyme (ACE) is a possible candidate gene that may influence both body fatness and blood pressure. Although several genetic studies have been conducted in adults, relatively few studies have examined the contribution of potential candidate genes, and specifically ACE I/D, on adiposity and BP phenotypes in childhood. Such studies may prove insightful for the development of the obesity-hypertension phenotype early in life. The purpose of this study was to examine differences in body fatness and resting blood pressure (BP) by ACE I/D genotype, and determine if the association between adiposity and BP varies by ACE I/D genotype in children. METHODS: 152 children (75 girls, 77 boys) were assessed for body composition (% body fat) using dual energy x-ray absorbtiometry and resting BP according to American Heart Association recommendations. Buccal cell samples were genotyped using newly developed PCR-RFLP tests for two SNPs (rs4341 and rs4343) in complete linkage disequilibrium with the ACE I/D polymorphism. Partial correlations were computed to assess the ociations between % body fat and BP in the total sample and by genotype. ANCOVA was used to examine differences in resting BP by ACE I/D genotype and fatness groups. RESULTS: Approximately 39% of youth were overfat based on % body fat (>30% fat in girls, 25% fat in boys). Body mass, body mass index, and fat-free mass were significantly higher in the ACE D-carriers compared to the II group (p < 0.05). BP was not significantly different by ACE I/D genotypes. In the total sample, correlations between adiposity and BP ranged from 0.30 to 0.46, and were not significantly different between genotypes. When grouped by genotype and body fat category, the overfat D-carrier subjects had significantly higher SBP and MAP compared to the normal fat D-carrier and normal fat II groups (p < 0.05). CONCLUSION: ACE D-carriers are heavier than ACE II children; however, BP did not differ by ACE I/D genotype but was adversely influenced in the overfat D-carriers. Further studies are warranted to investigate the genetics of fatness and BP phenotypes in children.

In overweight/obese but not in normal-weight women, polycystic ovary syndrome is associated with elevated liver enzymes compared to controls.

OBJECTIVE: To investigate liver enzymes in a cohort of women with Polycystic Ovary Syndrome (PCOS) and controls divided according to body mass index (BMI) and their association with features of the syndrome. DESIGN: Eighty-three PCOS women and 64 healthy women were studied. Patients and controls were subdivided into two groups, a lean subgroup (BMI <25kg/m(2)) and an overweight/obese subgroup (BMI >25kg/m(2)). Clinical history, height and weight were obtained and metabolic and hormonal parameters were determined. RESULTS: Serum fasting insulin, fasting glucose, HOMA-IR, triglycerides and total cholesterol were significantly higher (p<0.05) in women with PCOS compared to controls. No significant difference in serum liver enzymes levels between PCOS women and controls was detected. However, serum levels of alanine aminotransferase (ALT) (17.7 vs. 14.1 U/L, p<0.05) and gamma-glutamyl transpeptidase (gammaGT) (17.9 vs. 13.4 U/L, p<0.05) were significantly higher in overweight/obese PCOS women compared with overweight/obese controls. In overweight/obese PCOS patients and controls, ALT levels were positively correlated with free androgen index (FAI) (r=0.25 p<0.05) and total testosterone levels (r=0.33 p<0.01). CONCLUSIONS: The finding of elevated liver enzymes in overweight/obese PCOS women raises the question of screening for non-alcoholic fatty liver disease in this group.

Independent and opposite associations of trunk fat and leg fat with liver enzyme levels.

BACKGROUND: In contrast to trunk fat mass (TFM), which is associated with cardiovascular risk markers, leg fat mass (LFM) displays independent protective effects against atherosclerosis. Little is known about the respective influence of central and peripheral adiposity on liver enzyme levels. AIMS: To assess the respective influence of TFM and LFM on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) levels, and to test whether LFM might protect against an increase of liver enzyme levels. METHODS: Cross-sectional study on 1442 patients (women: 1155; men: 287) referred for overweight/obesity over 3 years. Body composition was analysed by dual-energy X-ray absorptiometry. The relationships among liver enzymes, age, weight, height, body mass index (BMI), biological indices and body composition were studied. RESULTS: The mean BMI was 39.7 +/- 7.9 kg/m(2) in women and 38.2 +/- 6.6 kg/m(2) in men. In women, after adjustement for confounding factors, ALT, AST and GGT were negatively and independently correlated with LFM and positively with TFM. Similar independent associations were observed for ALT and AST in men. The strongest associations were found for ALT in both women and men. CONCLUSIONS: As observed for cardiovascular risk factors, LFM and TFM are inversely and independently correlated with liver enzyme levels in obese patients. LFM may confer independent protective effects against obesity-associated liver damage.