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Background: Childhood obesity is often associated with non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in pediatrics., Methods: This multi-center study analyzed liver echogenicity and liver enzymes in relation to obesity, age, gender and comorbidities. Data were collected using a standardized documentation software (APV) from 1.033 pediatric patients (age: 4-18 years, body mass index = BMI: 28-36 kg/m 2 , 50% boys) with overweight (BMI >90th percentile), obesity (BMI >97th percentile) or extreme obesity (BMI > 99.5th percentile) and obesity related comorbidities, especially NAFLD from 26 centers of Germany, Austria and Switzerland. Liver enzymes aspartate aminotransferase (AST), alanine-aminotransferase (ALT) and gamma glutamyltransferase (gammaGT) were evaluated using 2 cut-off values a) > 25 U/L and b) > 50 U/L. Multiple logistic regression models were used for statistical analysis., Results: In total, 44% of the patients showed increased liver echogenicity. Liver enzymes > 25 U/L were present in 64% and > 50 U/L in 17%. Increased liver echogenicity was associated with elevated liver enzymes (> 25 U/L: odds ratio (OR) = 1.4, 95% CI: 1.1-1.9, P < 0.02; > 50 U/L: OR = 3.5, 95% CI: 2.4-5.1, P < 0.0001). Extreme obesity, adolescence and male gender were associated with increased liver echogenicity (extreme obesity vs overweight OR = 3.5, 95% CI: 1.9-6.1, P < 0.0001; age > 14 years vs age < 9 years OR = 2.2, 95% CI: 1.4-3.5, P < 0.001; boys vs girls OR = 1.6, 95% CI: 1.2-2.0, P < 0.001) and elevated liver enzymes (extreme obesity vs overweight > 25 U/L: OR = 4.1, 95% CI: 2.4-6.9, P < 0.0001; > 50 U/L: OR = 18.5, 95% CI: 2.5-135, P < 0.0001; age > 14 years vs age < 9 years > 50 U/L: OR = 1.9, 95% CI: 1.0-3.7, P > 0.05; boys vs girls > 25 U/L: OR = 3.1, 95% CI: 2.4-4.1, P < 0.0001; > 50 U/L: OR = 2.1, 95% CI: 1.5-2.9, P < 0.0001). Impaired glucose metabolism showed a significant correlation with elevated liver enzymes > 50 U/L (OR = 4.4, 95% CI: 1.6-11.8, P < 0.005). Arterial hypertension seemed to occur in patients with elevated liver enzymes > 25 U/L (OR 1.6, 95% CI: 1.2-2.0, P < 0.005)., Conclusions: NAFLD is strongly related to extreme obesity in male adolescents. Moreover impaired glucose tolerance was observed in patients with elevated liver enzymes > 50 U/L, but arterial hypertension was only present in patients with moderately elevated liver enzymes > 25 U/L.

Background Proopiomelanocortin (POMC) is a complex polypeptide that produces a variety of biologically active substances via cleavage in a tissue-specific manner [Challis BG, Millington GW. Proopiomelanocortin deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 1993-2018], yielding several products including adrenocorticotrophic (ACTH) and melanocyte stimulating hormones (MSH). These peptides have roles in the regulation of food intake, energy homeostasis, adrenal steroidogenesis, melanocyte stimulation and immune modulation. Rare mutations in the POMC gene can lead to ACTH deficiency and thus isolated hypocortisolism. The first cases of POMC mutation were documented by Krude et al. in 1998 [Krude H, Biebermann H, Luck W, Horn R, Brabant G, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155-7]. Mutations in the POMC gene were linked with a clinical phenotype of adrenal insufficiency, red hair pigmentation, early onset and rapidly progressive obesity, early onset type 2 diabetes, hypothyroidism, hypogonadism and growth hormone deficiency. Case presentation We describe a prepubertal Hispanic boy with a novel homozygous POMC mutation with severe obesity, hypothyroidism, adrenal insufficiency and abnormal reddish hair pigmentation. The patient presented as a 2-year-old with exponential weight gain, abnormal thyroid labs and speech delay. Laboratory testing demonstrated central adrenal insufficiency and genetic testing confirmed a homozygous mutation (nucleotide change c.20&#95;21ins25) in exon 3 of the POMC gene. Replacement therapy with thyroid hormone and hydrocortisone was coupled to a slight decrease in the rate of weight gain, although hyperphagia persisted. Parent-directed nutrition and activity education as well as attempts to restrict access to food resulted in a plateau of the body mass index (BMI). At 4 years of age, metformin treatment was initiated with the patient showing evolving signs of insulin resistance and failure of lifestyle/dietary intervention to adequately decrease the BMI. Over a 3-year metformin treatment span, the BMI decreased from 34.9 kg/m2 to 32.9 kg/m2. Conclusions We demonstrate a possible role for metformin in stemming progressive weight gain, thereby impacting the early onset obesity due to hyperphagia.

Background/objectives: Gamma-glutamyltranspeptidase (GGT) levels are an independent risk marker for the development of type 2 diabetes (T2DM). We investigated the relationship between the newly identified serum GGT fractions and glucose metabolism in obese subjects before and after bariatric surgery., Subjects/methods: Twenty-nine T2DM subjects, wait-listed for Roux-en-Y gastric bypass (RYGB; n = 21) or laparoscopic sleeve gastrectomy (LSG; n = 8), received a 5-h mixed meal test before (T0), 15 days (T15), and 1 year after surgery (T365). Insulin sensitivity was assessed by the OGIS index and β-cell function by C-peptide analysis; fractional GGT (b-, s-, m-, and f-GGT) analysis was performed by gel-filtration chromatography., Results: At T15, total GGT activity decreased by 40% after LSG (p = 0.007) but remained unchanged after RYGB. At T365, all patients showed a reduction in total GGT, in particular b-GGT (≥ 60%) and m-GGT (≥ 50%). In patients with biopsy-proven steatohepatitis (n = 10), total, b-, s-, and m-GGT fractions at T0 were significantly higher than in patients with low-grade steatosis (p = 0.016, 0.0003, and 0.005, respectively); at T365, there was a significant fall in total GGT as well as in each fraction in both groups. In a multiple regression model, b-GGT was the only fraction related to insulin sensitivity (p = 0.016; β coeff. = - 14.0) independently of BMI, fasting glucose, and triglycerides., Conclusions: While GGT activity is generally associated with impaired glucose metabolism, fractional GGT analysis showed that the b-GGT fraction specifically and independently tracks with insulin resistance.

Introduction; p to 300 million people have the body mass index (BMI) greater than 30 kg/m2. Obesity is the cause of many serious diseases, such as type 2 diabetes, hypertension, and non-alcoholic fatty liver disease (NAFLD). Bariatric surgery is the only effective method of achieving weight loss in patients with morbid obesity., Objectives: The aim of the study was to assess the impact of bariatric surgery on non-alcoholic fatty liver disease in patients operated on due to morbid obesity., Material and Methods: We included 20 patients who were qualified for bariatric procedures based on BMI &gt; 40 kg/ m2 or BMI &gt; 35kg/m2 with the presence of comorbidities. The average body weight in the group was 143.85kg, with an average BMI of 49.16kg/m2. Before the procedure, we evaluated the severity of non-alcoholic fatty liver disease in each patient using the Sheriff-Saadeh ultrasound scale. We also evaluated the levels of liver enzymes. Follow-up evaluation was performed twelve months after surgery., Results: Twelve months after surgery, the average weight was 102.34 kg. The mean %WL was 33.01%, %EWL was 58.8%, and %EBMIL was 61.37%. All patients showed remission of fatty liver disease. Liver damage, evaluated with ultrasound imaging, decreased from an average of 1.85 on the Sheriff-Saadeh scale, before surgery, to 0.15 twelve months after surgery (p &lt; 0.001). As regards liver enzymes, the level of alanine aminotransferase decreased from 64.5 (U/l) to 27.95 (U/l) (p &lt; 0.001), and the level of aspartate aminotransferase decreased from 54.4 (U/l) to 27.2 (U/l)., Conclusions: Bariatric procedures not only lead to a significant and lasting weight loss, but they also contribute to the reduction of fatty liver disease and improve liver function.

Background: Increased xanthine oxidase (XO) activity and uric acid levels are known to be associated with obesity and hypertension; however, it is not known if obesity is directly responsible for these associations in youth. This study investigated the effect of weight loss on XO activity, uric acid, and their relationship to blood pressure change in obese youth to provide greater insight on how obesity increases cardiovascular risk., Methods: This was an ancillary study in which 16 adolescents (mean age 15 ± 2 years) received meal replacement therapy over a period of four weeks. Outcomes measured at baseline and after intervention included weight, blood pressure, XO activity, plasma uric acid, uric acid clearance, and creatinine clearance., Results: After the meal replacement intervention, participants experienced reductions in body weight (109.2 ± 16 kg vs. 105.2 ± 14 kg, p < 0.0001) and BMI (38.7 ± 4 kg vs. 37.4 ± 3 kg, p < 0.0001). Plasma XO activity was reduced by 9.8% (p = 0.016). Uric acid clearance was decreased by 39% (p = 0.006). SBP (systolic blood pressure) and plasma uric acid concentrations were reduced but did not achieve statistical significance (p = 0.34 and 0.38, respectively). DBP (diastolic blood pressure) was unchanged (p = 0.86). No significant relationships were found between changes in blood pressure and changes in either XO activity or plasma uric acid levels., Conclusion: Weight loss led to decreases in uric acid production by lowering XO activity and decreases in uric acid clearance by reducing glomerular filtration (GF) and increasing reabsorption. Changes in XO activity and uric acid levels did not correlate with changes in blood pressure.

Semicarbazide-sensitive amine oxidase (SSAO), identical to primary amine oxidase or vascular adhesion protein-1, is a membrane enzyme that generates hydrogen peroxide. SSAO is highly expressed at the adipocyte surface, and its plasma levels increase with type 2 diabetes. Since visceral adipose tissue (AT) is more tightly associated with obesity complications than subcutaneous (SC) abdominal fat, we compared SSAO activity in plasma and 4 distinct AT locations in 48 severely obese women (body mass index (BMI), averaging 54 ± 11 kg/m 2 ), with or without a dysmetabolic profile. Higher glucose and triacylglycerol levels vs lower high-density lipoprotein (HDL)-cholesterol characterized dysmetabolic women (DYS; n = 25) from non-dysmetabolic (NDYS; n = 23), age- and weight-matched subjects. SC, mesenteric (ME), omental (OM), and round ligament (RL) fat locations were collected during bariatric surgery. SSAO capacity to oxidize up to 1 mM benzylamine was determined in AT and plasma with radiometric and fluorimetric methods. Plasma SSAO was higher in the DYS group. SSAO activity was higher in fat than in plasma, when expressed as radiolabeled benzaldehyde per milligram of protein. In ATs from DYS women, protein content was 10 % higher, and basal hydrogen peroxide release lower than in NDYS subjects, except for RL location. The SSAO affinity towards benzylamine did not exhibit regional variation and was not altered by a dysmetabolic profile (K m averaging 184 ± 7 μM; n = 183). Although radiometric and fluorimetric methods gave different estimates of oxidase activity, both indicated that AT SSAO activity did not vary according to anatomical location and/or metabolic status in severely obese women.

Background: Gastric resection, short bowel syndrome, and diabetes mellitus are risk factors for development of exocrine pancreatic insufficiency (EPI). Reasons are multifactorial and not completely elucidated., Objectives: To determine the prevalence of EPI after distal (dRYGB) and proximal Roux-en-Y gastric bypass (pRYGB) and to assess the influence of respective limb lengths., Setting: University hospital, Switzerland., Methods: The study comprised 188 consecutive patients who underwent primary dRYGB (common channel<120 cm, biliopancreatic limb 80-100 cm) or pRYGB (alimentary limb = 155 cm, biliopancreatic limb 40-75 cm) and who were followed-up for at least 2 years. Patients with a history of gastrointestinal or hepatobiliary resection (except for cholecystectomy), postoperative pregnancy, and any revision of RYGB (gastric pouch, limb lengths) were excluded. EPI was defined by clinical symptoms in combination with fecal pancreatic elastase-1<200 μg/g stool or fecal pancreatic elastase-1>200 and<500 μg/g stool and positive dechallenge-rechallenge test with pancreatic enzyme replacement therapy., Results: Mean follow-up was 52.2 months (range 24-120). Seventy-nine patients (42%) underwent dRYGB, and 109 (58%) underwent pRYGB. Of those, 59 (31%) patients were diagnosed with EPI after a mean 12.5±16.3 months. There was a significant difference between dRYGB and pRYGB groups in initial body mass index (dRYGB 47.1±8.1 kg/m(2) versus pRYGB 42.7±6.1 kg/m(2); P<.01), patients in Obesity Surgery Mortality Risk Score group C (13% versus 3%; P = .02), and prevalence of EPI (48% versus 19%; P<.01). Neither overall small bowel length nor absolute or relative limb lengths were influencing factors on EPI after dRYGB., Conclusion: Prevalence of EPI after dRYGB (48%) and pRYGB (19%) is of clinical importance. There was no significant difference in absolute or relative limb lengths between EPI and non-EPI groups after dRYGB., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

Background: Intrahepatic expression of dipeptidyl peptidase-4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non-alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity., Methods: cDPP4 was measured in 106 individuals with type 2 diabetes who had transient elastography (Cohort 1) and 145 individuals with morbid obesity who had liver biopsy (Cohort 2). Both cohorts had caspase-cleaved keratin-18 (ccK18) measured as a marker of apoptosis., Results: Natural log increases in cDPP4 activity were associated with increasing quartiles of ccK18 (Cohorts 1 and 2) and with median liver stiffness ≥10.3 kPa (Cohort 1) and significant fibrosis (F ≥ 2) on liver biopsy (Cohort 2)., Conclusions: In diabetes and/or obesity, cDPP4 activity is associated with current apoptosis and liver fibrosis. Given the pathogenic mechanisms by which DPP4 may progress NAFLD, measurement of cDPP4 activity may have utility to predict disease progression and DPP4 inhibition may improve liver histology over time., (© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Study Objectives: Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis., Design: Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia., Setting: The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School., Measurements and Results: In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion., Conclusions: The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease., (© 2015 Associated Professional Sleep Societies, LLC.)

Obese women with type 2 diabetes mellitus (T2DM) have more inflammation in their subcutaneous white adipose tissue (sWAT) than age-and-BMI similar obese women with normal glucose tolerance (NGT). We aimed to investigate whether WAT fatty acids and/or oxylipins are associated with the enhanced inflammatory state in WAT of the T2DM women. Fatty acid profiles were measured in both subcutaneous and visceral adipose tissue (vWAT) of 19 obese women with NGT and 16 age-and-BMI similar women with T2DM. Oxylipin levels were measured in sWAT of all women. Arachidonic acid (AA) and docosahexaenoic acid (DHA) percentages were higher in sWAT, but not vWAT of the T2DM women, and AA correlated positively to the gene expression of macrophage marker CD68. We found tendencies for higher oxylipin concentrations of the 5-LOX leukotrienes in sWAT of T2DM women. Gene expression of the 5-LOX leukotriene biosynthesis pathway was significantly higher in sWAT of T2DM women. In conclusion, AA and DHA content were higher in sWAT of T2DM women and AA correlated to the increased inflammatory state in sWAT. Increased AA content was accompanied by an upregulation of the 5-LOX pathway and seems to have led to an increase in the conversion of AA into proinflammatory leukotrienes in sWAT.

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76&#95;98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.

White adipose tissue has now been recognized as an important endocrine organ secreting bioactive molecules termed adipocytokines. In obesity, anti-inflammatory adipocytokines like adiponectin are decreased while pro-inflammatory factors are over-produced. These changes contribute to the development of insulin resistance and obesity-associated diseases. Since members of the casein kinase 1 (CK1) family are involved in the regulation of various signaling pathways we ask here whether they are able to modulate the functions of adiponectin. We show that CK1δ and ε are expressed in adipose tissue and that the expression of CK1 isoforms correlates with that of adiponectin. Furthermore, adiponectin co-immunoprecipitates with CK1δ and CK1ε and is phosphorylated by CK1δ at serine 174 and threonine 235, thereby influencing the formation of adiponectin oligomeric complexes. Furthermore, inhibition of CK1δ in human adipocytes by IC261 leads to an increase in basal and insulin-stimulated glucose uptake. In summary, our data indicate that site-specific phosphorylation of adiponectin, especially at sites targeted by CK1δ in vitro, provides an additional regulatory mechanism for modulating adiponectin complex formation and function., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Morbid obesity is associated with significant thrombophilia. Of interest, adipocytes obtained from obese patients have increased heme oxygenase (Hmox) activity, the endogenous enzyme responsible for carbon monoxide (CO) production. Given that CO enhances plasmatic coagulation, we determined whether morbidly obese patients undergoing bariatric surgery had an increase in endogenous CO and plasmatic hypercoagulability. CO was determined by noninvasive pulse oximetry measurement of carboxyhemoglobin (COHb). A thrombelastographic method to assess plasma coagulation kinetics and formation of carboxyhemefibrinogen (COHF) was utilized. Nonsmoking bariatric patients (n = 20, BMI 47 ± 8 kg/m, mean ± SD) had abnormally increased COHb concentrations of 2.7 ± 1.9%, indicative of Hmox upregulation. When coagulation kinetics of these bariatric patients were compared with values obtained from normal individuals' (n = 30) plasma, 70% (95% confidence interval 45.7-88.1%) had abnormally great velocity of clot formation, abnormally large clot strength, and COHF formation. Future investigation of Hmox-derived CO in the pathogenesis of obesity-related thrombophilia is warranted.

Background: Elevated serum aminotransferase levels are commonly associated with obesity and with a progression to chronic liver disease. Bariatric surgery is the most effective strategy to achieve weight loss., Methods: We conducted the present study with the aim of evaluating the influence of biliopancreatic diversion (BPD) on liver enzymes levels during 4 years in morbid obese patients with normal aminotransferase (n = 65) and in morbid obese patients with high aminotransferase basal levels (n = 50)., Results: A decrease in alanine aminotransferase and aspartate aminotransferase activities was significant after biliopancreatic diversion. The basal percentage of high aminotransferase levels and percentage of ratio ALT/AST <1 also decreased significantly at 1-, 2-, 3- and 4-years of follow-up in both groups. ALT (52 to 20%), AST (42 to 10%) and ALT/AST (80 to 22%) in patients with normal aminotransferase. ALT (82 to 20%), AST (70 to 6%) and ALT/AST (90 to 20%) in patients with elevated transaminase basal levels. Bariatric surgery was associated with a significant and sustained decrease in body weight in both groups. Serum trasnaminases level changes were positively correlated to body weight changes during follow-up., Conclusion: BPD is an effective method of achieving sustainable weight loss and reduced aminotransferase levels and enzyme ratios of liver damage., (© 2015 S. Karger AG, Basel.)

Context: Visceral adipose tissue (VAT) is a key contributor to chronic inflammation in obesity. The 12/15-lipoxygenase pathway (ALOX) is present in adipose tissue (AT) and leads to inflammatory cascades that are causal for the onset of insulin resistance in rodent models of obesity., Objective: The pathophysiology of the ALOX 12/15 pathway in human AT is unknown. We characterized the ALOX pathway in different AT depots in obese humans with or without type 2 diabetes (T2D)., Design: This study includes a cross-sectional cohort of 46 morbidly obese (body mass index >39 kg/m(2)) nondiabetic (n = 25) and T2D (n = 21) subjects., Setting: This study was conducted at Eastern Virginia Medical School (Norfolk, Virginia) in collaboration with Sentara Metabolic and Weight Loss Surgery Center (Sentara Medical Group, Norfolk, Virginia)., Patients: Twenty-five obese (body mass index 44.8 ± 4.4 kg/m(2)) nondiabetic (hemoglobin A1c 5.83% ± 0.27%) and 21 obese (43.4 ± 4.1 kg/m(2)) and T2D (hemoglobin A1c 7.66% ± 1.22%) subjects were included in the study. The subjects were age matched and both groups had a bias toward female gender., Main Outcomes and Measures: Expression of ALOX isoforms along with fatty acid substrates and downstream lipid metabolites were measured. Correlations with depot-specific inflammatory markers were also established., Results: ALOX 12 expression and its metabolite 12(S)-hydroxyeicosatetraenoic acid were significantly increased in the VAT of T2D subjects. ALOX 15A was exclusively expressed in VAT in both groups. ALOX 12 expression positively correlated with expression of inflammatory genes IL-6, IL-12a, CXCL10, and lipocalin-2., Conclusions: ALOX 12 may have a critical role in regulation of inflammation in VAT in obesity and T2D. Selective ALOX 12 inhibitors may constitute a new approach to limit AT inflammation in human obesity.

This study aimed to determine early postoperative changes of LDL/HDL subfraction profile and HDL-associated enzymes following laparoscopic sleeve gastrectomy (LSG). Thirteen obese patients (mean body mass index (BMI) 52.74 ± 10.97 kg/m(2)) underwent LSG and normal weight control patients (mean BMI 23.56 ± 1.92 kg/m(2)) underwent laparoscopic abdominal surgery. Fasting blood samples were collected prior to surgery, at day 1 after surgery, and after postoperation oral feeding. LDL and HDL subfraction analysis was done by continuous disk polyacrylamide gel electrophoresis. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay. Measurement of CETP and LCAT activity was performed via fluorometric analysis. LDL subfraction profile showed no change in both LSG and control group patients. No significant difference was observed in HDL cholesterol, HDL-subfraction distribution, and apoA-I levels in the control group. LSG patients showed a significant increase in HDL-large and a significant decrease in HDL-small fractions at postoperation day 1 compared to preoperation. HDL cholesterol significantly decreased and apoA-I significantly increased in LSG patients after postoperation oral feeding compared to both preoperation and postoperation day 1. Changes in HDL subfraction profile at postoperation day 1 after LSG were accompanied by a significant decrease in CETP protein, LCAT protein, and LCAT activity as compared to preoperation levels. Early changes in HDL subfraction profile and HDL-associated enzymes following LSG suggest that the surgical procedure, irrespective of changes in body weight, affects reverse cholesterol transport.

Purpose of Review: Despite a strong correlation between obesity and insulin resistance, 25% of severely obese (BMI >40) individuals are insulin sensitive. In this review, we will examine the factors in adipose tissue that distinguish the two groups, as well as reasons for believing the insulin-sensitive group will be less disease prone., Recent Findings: Obesity has been linked to the metabolic syndrome with an increase in visceral (intra-abdominal) compared to subcutaneous fat. Recent studies in which adipose tissue of insulin-sensitive and insulin-resistant patients with severe obesity were compared indicate that the insulin-resistant group is also distinguished by increases in oxidative stress and decreases in AMP-activated protein kinase (AMPK) activity. In contrast, changes in the expression of genes for SIRT1, inflammatory cytokines, mitochondrial biogenesis and function, and the two α-isoforms of AMPK showed more depot variation. Studies of how these and other changes in adipose tissue respond to bariatric surgery are still in their infancy., Summary: Available data suggest that increases in oxidative stress, decreases in AMPK activity and SIRT1 gene expression, depot-specific changes in inflammatory, mitochondrial and other genes distinguish adipose tissue of insulin resistant from insulin-sensitive individuals with severe obesity.

Background: Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that provides the majority of NADPH required for lipid biosynthesis. G6PD overexpression has been implicated in insulin resistance, hyperlipidemia, and increased oxidative stress in animals. This study examines G6PD expression in obese diabetic and nondiabetic subjects pre- and post-laparoscopic Roux-en-Y gastric bypass (LRYGB)., Methods: Patients undergoing LRYGB were recruited for the IRB-approved study and placed in either the diabetic (n = 11) or nondiabetic group (n = 16) (diabetic, HbA1c > 6.5%; nondiabetic, HbA1c < 6.0%). Blood samples were collected at baseline and throughout the first 3 postoperative months. Liver, adipose, and omental samples were taken during surgery. Results are expressed as mean ± SEM and were compared statistically using the Mann-Whitney test., Results: The two groups were not significantly different at baseline except for fasting glucose and HbA1c. G6PD activity (nm/min/mg protein) was significantly higher in red blood cells (RBCs) (3.12 ± 1.39 vs. 0.67 ± 0.14) and liver (17.23 ± 2.40 vs. 9.74 ± 2.18) in diabetics compared to nondiabetics. There was good correlation between increased liver G6PD activity and the severity of diabetes as measured by HbA1c (r (2) = 0.525) and fasting glucose (r (2) = 0.542). No significant difference was found in the adipose or omental G6PD expression. Both groups experienced a significant increase in G6PD blood activity shortly following surgery (1 week) followed by a reduction 3 months after surgery., Conclusion: These results are the first ever seen in human subjects and demonstrate increased G6PD activity in diabetics compared to nondiabetics. These results suggest a correlation between G6PD activity and the severity of type 2 diabetes. The early increases in G6PD activity after LRYGB were unexpected and longer follow-up is needed to determine the effects of LRYGB on G6PD activity.

Background: Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS)., Methods: Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5 years; BMI, 48.0 ± 3.6 kg/m(2)) and 36 women (mean age, 44.6 ± 1.9 years; BMI, 44.9 ± 1.2 kg/m(2)), were classified as having MS (MS+, n = 20) or not (MS-, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction., Results: Hepatic mRNA levels of these genes were higher in obese patients with MS (11β-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS- obese patients were compared., Conclusions: Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.

Gamma-glutamyl transferase (GGT) is a marker for cardiovascular risk and an independent predictor of long-term outcome in adults. Epidemiological data from pediatric cohorts are rare. We studied the association of GGT to body mass index as a standard deviation score, sex, and age in 68,415 children (age 11.7 ± 4.4 years; 48% boys; body mass index 27.2 ± 7.4 kg/m2; GGT measured in n = 23,955). GGT >50 U/L is strongly associated with extreme obesity (odds ratio 27.13, 95% confidence interval 15.07-48.85) and male sex (odds ratio 2.60, 95% confidence interval 2.03-3.31). GGT seems to be of clinical relevance and may be marketable as a surrogate in risk profiling for children with obesity.

Animal studies have revealed the association between stearoyl-CoA desaturase 1 (SCD1) and obesity and insulin resistance. However, only a few studies have been undertaken in humans. We studied SCD1 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from morbidly obese patients and their association with insulin resistance, sterol regulatory element binding protein-1 (SREBP-1) and ATPase p97, proteins involved in SCD1 synthesis and degradation. The insulin resistance was calculated in 40 morbidly obese patients and 11 overweight controls. Measurements were made of VAT and SAT SCD1, SREBP-1 and ATPase p97 mRNA expression and protein levels. VAT and SAT SCD1 mRNA expression levels in the morbidly obese patients were significantly lower than in the controls (P = 0.006), whereas SCD1 protein levels were significantly higher (P < 0.001). In the morbidly obese patients, the VAT SCD1 protein levels were decreased in patients with higher insulin resistance (P = 0.007). However, SAT SCD1 protein levels were increased in morbidly obese patients with higher insulin resistance (P < 0.05). Multiple linear regressions in the morbidly obese patients showed that the variable associated with the SCD1 protein levels in VAT was insulin resistance, and the variables associated with SCD1 protein levels in SAT were body mass index (BMI) and ATPase p97. In conclusion, these data suggest that the regulation of SCD1 is altered in individuals with morbid obesity and that the SCD1 protein has a different regulation in the two adipose tissues, as well as being closely linked to the degree of insulin resistance.

Severely obese subjects with the metabolic syndrome (MS) have higher dipeptidyl peptidase-4 (DPP4) expression in their visceral adipose tissue (VAT) compared to obese individuals without MS. We tested the hypothesis that methylation level of CpG sites in the DPP4 promoter CpG island in VAT was genotype-dependent and associated with DPP4 mRNA abundance and MS-related phenotypes. The VAT DNA was extracted in 92 severely obese premenopausal women undergoing biliopancreatic derivation for the treatment of obesity. Women were nondiabetic and none of them used medication to treat MS features. Cytosine methylation rates (%) of 102 CpG sites in the DPP4 CpG island were assessed by pyrosequencing of sodium bisulfite-treated DNA. Methylation rates were >10% for CpG sites 94-102. Their mean methylation rate (%Meth(94-102)) was different between genotypes for DPP4 polymorphisms rs13015258 (P = 0.001), rs17848915 (P = 0.0004), and c.1926 G>A (P = 0.001). The %Meth(94-102) correlated negatively with DPP4 mRNA abundance (r = -0.25, P < 0.05) and positively with plasma high-density lipoprotein (HDL) cholesterol concentrations (r = 0.22, P < 0.05), whereas DPP4 mRNA abundance correlated positively with plasma total-/HDL-cholesterol ratio (r = 0.25; P < 0.05). In the VAT of nondiabetic severely obese women, genotype-dependent methylation levels of specific CpG sites in the DPP4 promoter CpG island were associated with DPP4 gene expression and variability in the plasma lipid profile. Higher DPP4 gene expression in VAT and its relationship with the plasma lipid profile may be explained by actually unknown DPP4 biological effect or, to another extent, may also be a marker of VAT inflammation known to be associated with metabolic disturbances.

Adenine monophosphate (AMP) activated protein kinase (AMPK) is an important regulator of obesity. The objective of the present work was to study and compare AMPK protein expression in visceral vs. subcutaneous adipose tissue of morbid obese subjects and to correlate it with adipose tissue characteristics. We selected a total population of 17 extreme obese (BMI>or=40 kg/m2) aged 42.8+/-10.2 years were included in this study. We measured anthropometric and body composition parameters. Adiponectin expression by qRT-PCR, isoproterenol-stimulated lipolytic rates, and AMPK alpha subunits expression by Western blot in adipose tissue explants were determined. Finally plasma concentrations of glucose, triacylglycerols, total cholesterol, HDL-c, LDL-c and insulin were also measured. Our results showed that AMPK alpha expression was higher in subcutaneous than in visceral tissue. A positive correlation between AMPK expression and adiponectin expression in human subcutaneous adipose tissue was observed. Furthermore, a positive correlation between AMPK expression and isoproterenol evoked upregulation of lipolysis rate was also observed. In conclusion, AMPK alpha expression differed according to adipose tissue location. The positive correlation between subcutaneous adipose tissue AMPK and adiponectin or the evoked lipolysis rate could indicate a protective role of AMPK in this tissue, counteracting insulin resistance in morbid obese patients., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Background & Aims: Hepatocyte apoptosis is a key event in non-alcoholic steatohepatitis (NASH). We studied the effect of obesity on free fatty acid (FFA) levels, fatty acid transport proteins (FATPs) and on extrinsic and intrinsic activation of apoptosis in the liver., Methods: Liver biopsies were harvested from 52 morbidly obese patients [body mass index (BMI): 53.82+/-1.41; age: 45+/-10.50; 15 males/37 females] undergoing bariatric surgery, and were scored for NASH, evaluated for fibrosis, and investigated for intrahepatic expression of FATPs, death receptors and cytosolic apoptosis-related molecules. Findings were correlated with serum FFA levels and the degrees of intrahepatic (terminal dUTP nick end labelling) and systemic (M30) apoptosis., Results: In patients' liver sections, FATPs as well as select parameters of extrinsic and intrinsic apoptosis were found to be upregulated (CD36/FAT: x 11.56; FATP-5: x 1.33; CD95/Fas: x 3.18; NOXA: x 2.79). These findings correlated with significantly elevated serum FFAs (control: 14.72+/-2.32 mg/dl vs. patients: 23.03+/-1.24 mg/dl) and M30 levels (control: 83.12+/-7.46 U/L vs. patients: 212.61+/-22.16 U/L). We found correlations between FATPs and apoptosis mediators as well as with histological criteria of NASH and fibrosis., Conclusions: Increased FFA and FATPs are associated with extrinsically and intrinsically induced apoptosis, liver damage and fibrosis in obese patients. Thus, FATPs may offer an interesting new approach to understand and potentially intervene NASH pathogenesis.

Background: The enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes intracellular glucocorticoid reactivation by conversion of cortisone to cortisol in different tissues and have been implicated in several metabolic disorders associated with obesity. The aim of this study was to evaluate the 11beta-HSD1 expression in liver, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) in morbidly obese patients undergoing bariatric surgery and its correlations with clinical, anthropometric, and biochemical variables., Methods: A prospective study was conducted over a 27-month period. Hepatic, VAT, and SAT samples were obtained at the time of surgery. 11beta-HSD1 and 18S gene expression was measured using real-time quantitative reverse transcriptase-polymerase chain reaction., Results: Forty nine patients met the inclusion criteria [mean age: 42.2 +/- 10 years, body mass index (BMI): 42 +/- 6 kg/m(2), 71% women and 63% with metabolic syndrome (MS)]. 11beta-HSD1 mRNA levels were higher in liver than fat tissue (p < 0.001), being higher in SAT than in VAT (p < 0.001) without gender-specific differences. Hepatic expression of 11beta-HSD1 correlated positively with SAT and VAT, alanine aminotransferase (ALT), and serum glucose and was inversely associated with BMI. 11beta-HSD1 mRNA in VAT correlated positively with insulinemia, ALT, and LDL cholesterol. There were no associations between 11beta-HSD1 mRNA in SAT and the variables analyzed., Conclusions: 11beta-HSD1 expression is higher in liver in comparison to adipose tissue in obese patients. The observed correlations between hepatic and VAT 11beta-HSD1 expression with dyslipidemia and insulin resistance suggest that this enzyme might have a pathogenic role in obesity and related metabolic disorders.

Background: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme catalyzes interconversion of inactive cortisone to active cortisol. Its expression in adipose tissue has been associated with obesity and some of its metabolic disorders. Controversies regarding which fat depots [subcutaneous adipose tissue (SAT) or visceral adipose tissue (VAT)] have higher expression still remain. The aim of this work was to evaluate 11beta-HSD1 expression in SAT and VAT of obese patients and evaluate its association to metabolic features of metabolic syndrome., Methods: In 32 morbidly obese patients, paired samples of SAT and VAT were collected. All patients, 40.2+/-12.3 years and 36.7+/-3.8 body mass index (BMI), underwent sleeve gastrectomy or laparoscopic gastric bypass. Gene expression of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction. Spearman correlation test was used to evaluate relationships between 11beta-HSD1 levels and clinical and biochemical parameters., Results: 11beta-HSD1 mRNA levels were higher in SAT than in VAT, with median expression levels of 11.4 arbitrary units (AU) and 7.8 AU, respectively (p=0.03). SAT 11beta-HSD1 mRNA were correlated with VAT mRNA levels (r=-0.6, p=0.018) and hip circumference (r=0.66, p=0.018). SAT 11beta-HSD1 levels increase parallel according to BMI category. We did not find a correlation between SAT or VAT with fasting glucose (r=0.15, p=NS), total cholesterol (r=0.13, p=NS), triglycerides (r=0.04, p=NS), and high-density lipoprotein (r=-0.16, p=NS). However, SAT expression in patients with features of MS was higher than those without features of MS., Conclusions: Our results demonstrate that SATs express higher 11beta-HSD1 mRNA levels than VAT. This finding highlights the importance of SAT in obesity and its possible role on metabolic disorders associated with obesity.

Background: Most patients with morbid obesity develop non-alcoholic fatty liver disease (NAFLD). The origins of lipid deposition in the liver and the effects of bariatric surgery in the obese with NAFLD are controversial., Methods: We analyzed lipids and lipoprotein lipase (LPL) in both plasma and liver biopsies performed before and 12-18 months after Roux-en-Y gastric bypass surgery in 26 patients., Results: In the livers of morbidly obese patients, the levels of LPL messenger RNA (mRNA) were higher (4.5-fold) before surgery than afterwards than control livers. In these patients, LPL activity was also significantly higher (91 +/- 7 mU/g) than in controls (51 +/- 3 mU/g, p = 0.0026) and correlated with the severity of the liver damage. All hepatic lipids were significantly increased in obese patients; however, after bariatric surgery, these lipids, with the exception of NEFA, tended to recover to normal levels., Conclusions: The liver of obese patients presented higher LPL activity than controls, and unlike the controls, this enzyme could be synthesized in the liver because it also present LPL mRNA. The presence of the LPL activity could enable the liver to capture circulating triacylglycerides, thus favoring the typical steatosis observed in these patients.

The incretin system has been shown to stimulate insulin secretion in a glucose dependent manner and currently fosters considerable hope for the treatment of diabetes. Recently, we have shown that the dipeptidylpeptidase-4 (DPP4) gene, which is responsible for incretin inactivation, was overexpressed in omental adipose tissue of obese men with the metabolic syndrome, compared to men not characterized by this condition. Since the cardiovascular disease (CVD) risk profile shows substantial inter-individual variability in obesity, this study aimed at verifying whether DPP4 polymorphisms contribute to explain such a difference. In the first step of this multi-stage study, seven tagging SNPs were genotyped in a sample of 576 obese (BMI>40 kg/m(2)) individuals and tested for their association with blood pressure and lipids, as well as diabetes-related phenotypes. Then, in an additional sample of 572 obese individuals (stage 2), SNPs showing trends (P<0.10) for an association in the first sample were genotyped and reanalyzed. Logistic regressions were used to compute odds ratio for obesity-related metabolic complications. In sample 1, homozygotes for rs17848915 and rs7608798 minor alleles were at lower risk of hyperglycemia/diabetes (P=0.002) and elevated plasma triglyceride levels (P=0.030) respectively, whereas rs1558957 heterozygotes were at higher risk to have high plasma triglyceride (P=0.040), HDL- (P=0.021), LDL- (P=0.001) and total-cholesterol (P=0.003) levels. However, none of these associations was consistently replicated in stage 2. This first comprehensive genetic analysis does not support the notion that DPP4 polymorphisms could modulate the CVD risk profile among obese patients.

Growth hormone [GH] administration results in a reduction in adiposity of humans that is attributed to stimulation of lipolysis. We examined the effect of direct addition of human GH, in both the absence and presence of dexamethasone [Dex], as well as that of interferon beta on lipolysis by omental adipose tissue explants from obese women incubated for 48h in primary culture. There was a significant stimulation of lipolysis by GH in the presence of Dex but not by Dex or GH alone. There was also a significant further stimulation by GH in the presence of Dex of hormone-sensitive lipase, perilipin, lipoprotein lipase and beta1 adrenergic receptor mRNA. We conclude that the direct lipolytic effect of GH is accompanied by an increase in HSL mRNA in the presence of DEX, but GH also increased the mRNAs for other proteins that could explain all or part of its lipolytic action.

Objective: To identify factors associated with raised alanine transaminase, aspartate transaminase, and gamma-glutaryl transferase in severely obese children, Patients and Methods: In all, 201 children with early-onset obesity and greater than 140% ideal weight for height were recruited. Anthropometric and body fat measurements, fasting blood tests, and oral glucose tolerance tests were performed., Results: The mean and standard deviation (SD) for age was 11.1 (3.0) years, for weight for height 170.5% (22.7%), and for percentage body fat was 40.7% (5.2%). Elevated liver transaminases were present in 53 subjects (26.4%), who were therefore at risk for nonalcoholic fatty liver disease, and was associated with male sex (odds ratio [OR] 2.144, 95% confidence interval [CI] 1.033-4.448), Chinese ethnicity (OR 2.062, 95% CI 1.038-4.096), reduced physical activity (OR 2.389, 95% CI 1.163-4.909), insulin resistance (P < 0.05), elevated triglyceride levels (P = 0.029), and increased waist-hip ratio (P = 0.005). Stepwise logistic regression analysis of the main factors as covariates revealed Chinese ethnicity, waist-hip ratio, reduced physical activity, and homeostasis model assessment index were significant predictors. Alanine transaminase/aspartate transaminase were not well correlated with percentage body fat and weight for height. Subjects with type 2 diabetes mellitus and impaired glucose tolerance were more likely to have raised hepatic transaminases (OR 6.176, 95% CI 1.326-28.754). The severity of metabolic syndrome correlated with increasing aspartate transaminase, alanine transaminase, and gamma-glutaryl transferase (P < 0.01)., Conclusions: Insulin resistance, truncal adiposity, and physical inactivity are major determinants potentially modifiable to reduce risk of nonalcoholic fatty liver disease. Increasing physical activity levels were associated with decreasing insulin resistance and transaminases, despite lack of correlation with waist-hip ratio, which supports the direct benefit of regular physical activity in preventing nonalcoholic fatty liver disease.

Diagnosis and treatment of common conditions in morbidly obese patients still pose a challenge to physicians and surgeons. Sometimes too much reliance is put on investigations that can lead to a misdiagnosis. This case demonstrates an obese woman admitted under the medical team with a presumed diagnosis of pneumonia, who was later found to have an acute abdomen and raised amylase, which led to an assumed diagnosis of pancreatitis. She died within 24 h of admission and post mortem confirmed the cause of death as systemic sepsis due to perforated appendicitis, with no evidence of pancreatitis. Significantly elevated serum amylase level may occur in non-pancreatitic acute abdomen.

Objective: Severe juvenile obesity causes metabolic and cardiovascular complications in adulthood. The catalytic p110beta subunit of phosphatidyl-inositol-3 kinase is a major effector of insulin action. We studied the p110beta gene as a candidate gene for association with insulin resistance (IR) and fasting glycemia in severely obese children., Methods: We conducted an association study in 580 severely obese European children (body mass index > 99.6th centile) and 606 nonobese control children, in whom glucose and insulin were measured in the fasting state. The homeostasis model assessment insulin resistance index was used to estimate IR., Results: We found that a single-nucleotide polymorphism (rs361072) located in the promoter of the p110beta gene was associated with fasting glucose (P = 0.0002), insulin (P = 2.6 10(-8)), and homeostasis model assessment insulin resistance index (P =1 10(-9)) in the severely obese children. The effect of rs361072 was marginal or not significant in nonobese children., Conclusions: The C allele of rs361072 attenuates IR in superobese children.

Elevations in branched-chain amino acids (BCAAs) in human obesity were first reported in the 1960s. Such reports are of interest because of the emerging role of BCAAs as potential regulators of satiety, leptin, glucose, cell signaling, adiposity, and body weight (mTOR and PKC). To explore loss of catabolic capacity as a potential contributor to the obesity-related rises in BCAAs, we assessed the first two enzymatic steps, catalyzed by mitochondrial branched chain amino acid aminotransferase (BCATm) or the branched chain alpha-keto acid dehydrogenase (BCKD E1alpha subunit) complex, in two rodent models of obesity (ob/ob mice and Zucker rats) and after surgical weight loss intervention in humans. Obese rodents exhibited hyperaminoacidemia including BCAAs. Whereas no obesity-related changes were observed in rodent skeletal muscle BCATm, pS293, or total BCKD E1alpha or BCKD kinase, in liver BCKD E1alpha was either unaltered or diminished by obesity, and pS293 (associated with the inactive state of BCKD) increased, along with BCKD kinase. In epididymal fat, obesity-related declines were observed in BCATm and BCKD E1alpha. Plasma BCAAs were diminished by an overnight fast coinciding with dissipation of the changes in adipose tissue but not in liver. BCAAs also were reduced by surgical weight loss intervention (Roux-en-Y gastric bypass) in human subjects studied longitudinally. These changes coincided with increased BCATm and BCKD E1alpha in omental and subcutaneous fat. Our results are consistent with the idea that tissue-specific alterations in BCAA metabolism, in liver and adipose tissue but not in muscle, may contribute to the rise in plasma BCAAs in obesity.

Background and Aims: Recent studies have shown an association between obstructive sleep apnea (OSA) and elevated liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the current study was to compare biochemical and histologic findings in patients with NAFLD as a function of OSA status., Methods: Subjects consisted of 85 patients who had a sleep study followed by a liver biopsy performed at the time of obesity surgery. The diagnosis of OSA was based on an apnea hypopnea index of >/=15. Demographic and laboratory data were collected retrospectively. Liver biopsies were systematically evaluated for features of NAFLD including degree of steatosis, inflammation, and fibrosis., Results: All but one patient had histologic evidence of NAFLD and 51% of the study population had OSA. A higher proportion of patients with OSA had elevated alanine aminotransferase levels (13/39) compared with those without OSA (3/34) (P=0.01). Only 19% of subjects had fibrosis on liver biopsy and still fewer (5%) had bridging fibrosis or cirrhosis. There was a trend toward a higher prevalence of OSA in patients with evidence of progressive liver disease, as indicated by inflammation plus fibrosis (11/15), compared with those with inflammation alone (22/48) (P=0.06)., Conclusions: In obese patients with NAFLD, OSA was associated with elevated alanine aminotransferase levels and a trend toward histologic evidence of progressive liver disease.

Background and Aims: An elevation in liver enzymes and, most notably, high serum alanine aminotransferase (ALT) activity, has been correlated with metabolic syndrome and obesity. However, whether obesity per se or obesity-related co-morbidities affect aminotransferase activity is still unclear. In this study we sought to evaluate serum aminotransferase activity in morbid and uncomplicated obese subjects, Methods: In this cross-sectional study, serum aminotransferase activity, anthropometric and metabolic parameters were assessed in 290 morbid and 105 uncomplicated consecutive obese subjects matched for body mass index (BMI) (40.1+/-6.8 vs. 39.9+/-8.3 kg/m(2), respectively), age (35.9+/-10 vs. 34.8+/-9.6 years, respectively), sex distribution and duration of obesity., Results: Uncomplicated obese subjects showed significantly lower serum ALT activity (17.58+/-6.3 (range 10-39) vs. 23.43+/-16 (range 12-89) U/l, (p<0.001)), and lower aspartate aminotransferase (AST), AST/ALT ratios and gamma-glutamyltranspeptidase (gammaGT) (p<0.01 for all) than morbid obese subjects. Only 11% women and 19% men in the uncomplicated obese group showed high ALT levels, while ALT activity was high in 48% women and 51% men in the morbid obese group. Fasting insulin was the best correlate of ALT activity (R(2)=0.21, p=0.003)., Conclusions: Our findings show that elevated ALT and AST activity are associated with increased fasting insulin and not with obesity per se, suggesting that the presence of insulin resistance, rather than BMI alone, plays a role in mediating the increased aminotransferase activity.

Background: The authors examine the mitochondrial electron transport system (ETS) with regard to caloric restriction and body size in humans., Methods: The study population included 59 morbidly obese (MO) female subjects with mean body mass index (BMI) 49.6 +/- 1.7 and 40 age-matched previously morbidly obese patients with surgically-induced caloric restriction (SCR) and mean BMI 28.9 +/- 1.1. ETS function in the 2 study groups were made by measuring their lymphocyte mitochondrial ETS complexes I-IV activities and complex III binding kinetics. Linear regression analyses were used to analyze the interactions between ETS function and BMI, energy intake, and metabolic status., Results: The MO, as compared to SCR, subjects had significantly (P < 0.01) higher ETS complexes II-IV activities (complex II = 20.4 +/- 1.9 vs 15.3 +/- 1.1, complex III = 129.4 +/- 10.1 vs 72.3 +/- 4.9, complex IV = 3.1 +/- 0.3 vs 1.4 +/- 0.1 nmol/mg/min for the MO vs SCR, respectively). ETS complexes activities were positively and significantly correlated with subjects' BMI, carbohydrate caloric intake, and fasting plasma insulin levels. Michaelis-Menten kinetic analysis showed that the Km for ubiquinol-2 in complex III of MO patients was 2-fold greater than SCR values, reflecting an apparent reduction in substrate binding capacities producing a resistance to electron flow in the MO population. Caloric consumption, carbohydrate calories, insulin levels, and BMI were also each significantly (P < 0.05) and positively correlated with the Km of Complex III., Conclusions: ETS function and efficiency are compromised by increasing BMI and caloric consumption in morbidly obese women, and caloric restriction may reduce the potential for excessive oxidative free radical generation via the ETS.

Background: Morbid obesity is a risk factor of nonalcoholic steatohepatitis (NASH). Obstructive sleep apnea (OSA) could also be an independent risk factor for elevated liver enzymes and NASH. The relationships between liver injuries and OSA in morbidly obese patients requiring bariatric surgery were studied prospectively., Methods: Every consecutive morbidly obese patient (BMI > or =40 kg/m2 or > or =35 kg/m2 with severe comorbidities) requiring bariatric surgery was included between January 2003 and October 2004. Polygraphic recording, serum aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT) and liver biopsy were systematically performed. OSA was present when the apnea-hypopnea index (AHI) was >10/h., Results: 62 patients (54 F; age 38.5 +/- 11.0 (SD) yrs; BMI 47.8 +/- 8.4 kg/m2) were included. Liver enzymes (AST, ALT or GGT) were increased in 46.6%. NASH was present in 34.4% and OSA in 84.7%. Patients with OSA were significantly older (P = 0.015) and had a higher BMI (P = 0.003). In multivariate analysis, risk factors for elevated liver enzymes were the presence of OSA and male sex. The presence of NASH was similar in patients with or without OSA (32.7% vs 44.4% of patients, P = 0.76)., Conclusion: In this cohort of morbidly obese patients requiring bariatric surgery, one-third of patients had NASH, a prevalence similar to previous studies. OSA was found to be a risk factor for elevated liver enzymes but not for NASH.

Background: Rhabdomyolysis (RML) is a recently recognized complication of bariatric operations, but it is not known whether creatine kinase (CK) levels along with clinical markers are able to define the course and outcome., Methods: Bariatric patients (n=324) were reviewed retrospectively. Substantially elevated plasma CK after operation was identified in 4.9% (16/324). The affected population was divided into Group I (n=11, 68.8%) with CK 1050-8000 IU/L and no conspicuous muscle pain, weakness or swelling, and Group II (n=5, 31.2%) displaying CK >8000 IU/L and severe pain and dysfunction. The main outcome measures were CK concentration, frequency of renal failure, need for hemodialysis and mortality., Results: Group I subjects compared to Group II were younger (37.7 +/- 10.9 vs 44.0 +/- 5.5 years, P<0.05) and predominantly females (72.7% vs 40.0%, P<0.05). Peak CK values were definitely lower (2811 +/- 952 vs 28136 +/- 19000 IU/L, P<0.001), and none progressed to renal failure (0% vs 40.0%, P<0.05). No difference was detected regarding preoperative BMI (50.8 +/- 8.1 vs 54.6 +/- 7.0 kg/m(2), NS), duration of operation (5.3 +/- 1.6 vs 5.6 +/- 2.1 hours, NS) or types of anesthetic drugs (basically fentanyl, nitrogen oxide and halothane/isoflurane)., Conclusions: 1) Demographic features, nominally gender and age, were different between the two degrees of RML; 2) Renal failure and hemodialysis were a danger only in patients with massive CK elevation and muscle pain; 3) Moderate CK increase was very well tolerated and rarely entailed major clinical symptoms; 4) Early diagnosis, fluid replenishment and general supportive therapy probably contributed to avert mortality.

Objective: The objective of this study was to investigate the consequences of low dietary folate intake and the impact of the 677 C-->T methylenetetrahydrofolate reductase (MTHFR) common mutation on liver function in obese adolescents., Methods: Fifty-seven obese girls (BMI = 36.1 +/- 6.0 kg/m) aged 14.1 +/- 1.5 years were included before starting a weight reduction program. Dietary intakes for folate were assessed by means of an adapted food frequency questionnaire (n = 50). Liver enzymes, plasma lipids, glucose metabolism parameters, ferritin, homocysteine and erythrocyte folate content were measured in plasma or blood obtained under fasting conditions. The MTHFR 677 C-->T polymorphism, which is associated with decreased enzyme activity, was determined using PCR. Body composition was assessed using dual x-ray absorptiometry., Results: Twenty-three subjects were heterozygote (CT) for the mutation and 5 were homozygote (TT). An increase in alanine amino transferase (ALT) and ALT/aspartate aminotransferase ratio was associated with the mutation (F = 4.46, P = 0.016 and F = 5.92, P = 0.0049, respectively). Alanine amino transferase was correlated negatively to folate intake (r = -0.32, P = 0.024) (n = 50) and positively to homocysteine concentrations (r = 0.30, P = 0.025). Body composition was similar among the 3 genotypic groups. Ferritin was also correlated to ALT concentrations of the entire group (P = 0.009)., Conclusion: Our data suggest that folate intake and the MTHFR polymorphism represent a part of the link between antioxidant status and liver disease in obese adolescent girls.

Background: Increased activity of the immuno-modulatory enzyme indoleamine-2,3-dioxygenase (IDO) during immune activation, results in tryptophan depletion. Tryptophan metabolic changes reduce serotonin production and cause mood disturbances, depression, and impaired satiety, ultimately leading to increased food intake and obesity. Bariatric surgery significantly diminishes immune mediators by substantial weight reduction. We examined IDO-mediated tryptophan-catabolism in morbidly obese patients compared to lean individuals., Methods: Serum concentrations of kynurenine and tryptophan, calculated kynurenine to tryptophan ratios (kyn trp-1) as an indirect estimate of IDO activity, and neopterin levels reflecting IFN-gamma mediated immune activation, were assessed before and after bariatric surgery. The study population included 22 morbidly obese individuals and 20 normal-weight volunteers., Results: Median weight loss after 24.4+/-5.1 months was 40.6 kg resulting in a reduction of BMI from 44.1 kg/m(2) to 29.9 kg/m(2) (P<0.001). Preoperative kyn trp-1 in morbidly obese patients was significantly increased compared to the control group (41.6+/-20.1 mmol/mol vs 26.5+/-5.1 mmol/mol; P<0.001). Postoperative weight reduction did not lead to normalization of kyn trp-1 (37.9+/-14.0 mmol/mol). As a consequence, tryptophan levels were significantly lower in morbidly obese patients (pre-: 51.5+/-9.2 micromol L(-1) and postoperatively: 46.9+/-7.6 micromol L(-1)) when compared with those of normal-weight controls (64.8+/-9.5 micromol L(-1); P<0.001). In addition, neopterin levels were elevated in the study population pre- and postoperatively compared to normal-weight volunteers (both P<0.001)., Conclusions: Tryptophan depletion in morbidly obese patients is due to chronic immune activation and persists in spite of significant weight reduction following bariatric surgery. This might thereby be responsible for diminished serotonin functions, leading to unchanged satiety dysregulation and a reward-deficiency-syndrome.

We have reported that the rate of de novo triglyceride (TG) synthesis by omental, but not subcutaneous, adipose tissue was higher in African-American women (AAW) than in Caucasian women (CAW). The purpose of this study was to explore the potential mechanisms underlying this increase. Toward that end, we determined the activities of key enzymes in the pathway of TG synthesis, the rates of uptake of fatty acids by adipocytes, mRNA and protein levels of the fatty acid-transporting proteins FAT/CD36 and FATP, and mRNA and protein levels of PPARgamma in omental fat of AAW and CAW. The results showed 1) no difference in the activity of phosphofructokinase, glycerol-3-phosphate dehydrogenase, or diacylglycerol acyltransferase; 2) a higher rate of fatty acid uptake by adipocytes of the AAW; 3) an increase in the mRNA and protein levels of CD36 and FATP4 in the fat of the AAW; and 4) an increase in the mRNA and protein levels of PPARgamma, which can stimulate the expression of CD36 and FATP. These results suggest that the increase in the transport of fatty acid, which is mediated by the overexpression of the transport proteins in the omental adipose tissue of the AAW, might contribute to the higher prevalence of obesity in AAW.

The upper limit of normal for ALT activity has been recommended to be lowered to < or = 30 U/L in men and < or = 19 U/L in women. These changes have been suggested to be diagnostically useful in subjects with nonalcoholic fatty liver disease (NAFLD). Our aim was to investigate the prevalence and spectrum of NAFLD with regard to the new ALT guidelines in 233 women with class II/III obesity. We compared our prior reference range for ALT (ULN < or = 30 U/L in women) with the new standard. Our study demonstrates that only 86 patients (36.9%) would be classified as having normal ALT levels compared with 169 patients (72.5%) by the new and old standards, respectively. In patients with normal ALT activity (new vs. old standard), the prevalence of fatty liver (FL: 39.5% vs 40.2%), portal fibrosis, and steatosis (IPF: 37.2% vs. 33.7%) and nonalcoholic steatohepatitis (NASH: 23.3% vs. 26%) were similar. In comparison, newly defined patients with elevated ALT levels (>19 U/L) demonstrated an increased prevalence of FL (36%) and IPF (11.6%) but a 23.8% decrease in the prevalence of NASH as compared with the old standard. The sensitivity and specificity for NASH were 42% and 80% (ALT > 30 U/L) compared with 74% and 42% (ALT > 19 U/L). In conclusion, a significant increase in the prevalence of FL and IPF is detected in subjects with elevated ALT levels with the application of the new standard. However, the diagnostic utility for ALT to identify NASH or IPF remains poor, and significant healthcare expenditures may be incurred if this standard is adopted.

Aims/hypothesis: The development of insulin resistance may contribute to the occurrence and progression of the metabolic syndrome associated with obesity. Components contributing to the insulin pathway and its regulation are good candidates for the molecular study of metabolic syndrome pathogenesis. Protein tyrosine phosphatase 1B (PTP 1B) is an important negative regulator of insulin. We investigated whether PTP 1B SNPs are associated with obesity and obesity-related traits as well as global metabolic syndrome in morbidly obese subjects., Methods: Untranslated and coding regions of the PTP 1B gene were screened in groups of non-diabetic and diabetic obese subjects and in non-obese subjects. Unrelated morbidly obese ( n=711) and non-obese ( n=427) French Caucasian subjects were genotyped for a case-control study., Results: Six SNPs were identified: two rare variants were located in 5'UTR (-109 C>T and -69 C>T), two in the intronic regions (IVS3+38 G>T and IVS5+3666delT) and two have been described previously (P303P in exon 8 and P387L in exon 9). A case-control study showed an association between the frequent IVS5+3666delT SNP and obesity ( p=0.02). In the obese group, associations between PTP 1B SNPs and features of dyslipidaemia were found. P303P was associated with lower apolipoprotein A1 levels ( p=0.05) whereas P387L was associated with higher triglyceride ( p=0.0003), apolipoprotein B ( p=0.09) and lipoprotein a concentrations ( p=0.006)., Conclusions/interpretation: Our results support the hypothesis that the PTP 1B gene contributes to the polygenic basis of obesity. PTP 1B SNPs may interact with environmental factors to induce more severe phenotypes, e.g. atherogenic dyslipidaemia, in morbidly obese subjects.

Objective: A relationship between free fatty acids, intramuscular triglycerides (TG(M)s), and insulin resistance is widely accepted. The intracellular level of malonyl-coenzyme A (CoA) was suggested to be the possible link. Acetyl-CoA carboxylase (ACC) is a key enzyme in fatty acid metabolism, catalyzing the synthesis of malonyl-CoA, a fatty acid acyl-chain elongation unit, from acetyl-CoA. We assessed ACC2 mRNA expression variations in skeletal muscle of subjects who have undergone biliopancreatic diversion (BPD) operation. BPD, in fact inducing a massive lipid malabsorption, leads to a reversion of insulin resistance., Research Methods and Procedures: Twelve obese women (BMI > 40 kg/m(2)) were enrolled in the study. Body composition, euglycemic-hyperinsulinemic clamp, and muscle biopsies for lipid analysis and reverse transcription-competitive polymerase chain reaction were performed before and 3 years after BPD., Results: The average weight loss was around 37%. A significant inverse linear relation was observed between glucose uptake and TG(M) (y = -5.62x - 142.82, R(2) = 0.50, p = 0.01). The reduced amount of ACC2 mRNA directly correlated with both TG(M) (y = 2.11x +69.85, R(2) = 0.70, p = 0.01) and fasting insulin (y = 1.49x + 57.17, R(2) = 0.69, p < 0.01) concentrations., Discussion: In conclusion, down-regulation of ACC2 mRNA, induced by the lowering of plasma insulin concentration, is related to improvement of insulin sensitivity. We hypothesize that reduced amount of malonyl-CoA, consequent to reduced ACC2 mRNA, enhancing fatty acid oxidation, causes lowering of the intramyocitic triglyceride depot.

Despite the effects of hyperinsulinemia and hyperglycemia, 2 factors known to inhibit endogenous glucose production (EGP) in nondiabetic subjects, increased EGP is a consistent feature of type 2 diabetes. Recent studies have suggested that increased glucose-6-phosphatase (G6Pase) and/or decreased glucokinase (GK) may explain the increase in EGP. However, no studies to date have clearly established this relationship in type 2 diabetes. The present studies were designed to determine rates of EGP and the activities of G6Pase and GK in obese patients scheduled for gastric bypass surgery. The study group consisted of 14 obese nondiabetic subjects and 13 patients with type 2 diabetes (BMI 53.7 +/- 2.4 vs. 50.1 +/- 1.6 kg/m2). Rates of EGP were determined after an overnight fast with a 4-h infusion of [6,6]-D-glucose, and they were significantly higher in the type 2 diabetic patients (85.9 +/- 10.0 vs. 137.8 +/- 14.4 mg x m(-2) x min(-1), P < 0.001) despite greater plasma glucose (5.1 +/- 0.1 vs. 12.0 +/- 1.1 mmol/l) and similar insulin concentrations (130.8 +/- 19.8 vs. 112.8 +/- 16.2 pmol/l, NS). Moreover, resistance to insulin-induced suppression of EGP was observed in the patients with type 2 diabetes when insulin concentrations were increased from approximately 120 to 180 pmol/l. Hepatic G6Pase activity determined from freshly isolated microsomes was significantly increased in the type 2 diabetic patients compared with the obese control subjects (0.16 +/- 0.02 vs. 0.09 +/- 0.01 micromol x min(-1) x mg(-1) protein, P < 0.02), whereas levels of GK were decreased (1.20 +/- 0.16 vs. 2.01 +/- 0.01 micromol x min(-1) x mg(-1) protein, P < 0.01). Net flux through G6Pase was significantly increased in type 2 diabetic patients (P < 0.01). We conclude that increased EGP is mediated in part by increased G6Pase flux in type 2 diabetes.

Oubain sensitive and insensitive adenosine triphosphatase showed decrease in their activities in the polymorphonuclear leukocytes of obese patients while the activity of acetylcholinesterase was found to be increased significantly. The contents of sodium, potassium and magnesium were found to be significantly decreased in polymorphonuclear leukocytes of obese patients. Polymorphonuclear leukocytes obtained from treated obese patients showed considerable restoration.

In adult obese patients both an increase of aminotranspherase values and hepatic steatosis have been frequently showed. Conversely in childhood the existence of a liver's damage is often not investigated. To assess the prevalence of hepatic alterations in obese children, we studied 135 subjects, all affected by simple obesity, showing in a 20% of them the presence of ultrasonographic evidence of hepatic steatosis and/or hyperaminotransferasemia. Our study demonstrates the existence of silent hepatic alterations also in obese children and suggests to improve the treatment of obesity in childhood to prevent the progression of liver's damage.

Studies examining animal models of genetic obesity have identified defects in adipocyte hormone-stimulated lipolysis that involve the adenylate cyclase transmembrane signaling system, specifically those components that decrease adenylate cyclase activity. To determine whether obese people demonstrate alterations in adenylate cyclase activity that could contribute to the maintenance of obesity by inhibiting lipolysis, we examined human adipocytes from patients who were lean, obese, or formerly obese. Fat samples were obtained from the lower abdomen of 14 women who were morbidly obese (obese group), from 10 women who were formerly morbidly obese and had lost weight after gastric stapling (postobese group), and from 10 similarly aged women of normal weight (controls). Adipocyte adenylate cyclase activity was determined under ligand-free (no stimulatory or inhibitory influences present), hormone-stimulated (isoproterenol, 10(-6) mmol/L), and maximal (cells stimulated with 10 mumol/L forskolin) conditions by measuring cyclic adenosine monophosphate (cAMP) levels by radioimmunoassay. The activity of adenylate cyclase was significantly different (p less than 0.01) in the three groups. Adipocytes from obese women had lower levels of cyclase activity under both ligand-free (5% vs 16% of maximal) and hormone-stimulated conditions (76% vs 100% of maximal) than adipocytes from normal women. Postobese women had levels of hormone-stimulated cAMP identical to those of normal women but still had abnormal ligand-free levels (under 5%). These results suggest the presence of an alteration in adipocyte adenylate cyclase regulation in morbidly obese women that is not entirely corrected when weight is lost after food intake is reduced by gastric stapling. This alteration in ligand-free cAMP activity may contribute to the development and maintenance of obesity.