Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Insulin Resistance and CGM-Derived Parameters in People With Type 1 Diabetes: Are They Associated?

BACKGROUND: Insulin resistance (IR) is increasingly more prevalent in people with type 1 diabetes (T1D). OBJECTIVE: We investigated whether IR is associated with continuous glucose monitor (CGM)-derived parameters (glucometrics), such as time in range (TIR), time above range (TAR), time below range (TBR), and glycemic variability (CV). METHODS: This is a retrospective analysis of 2 databases: IR was quantified according to the estimated glucose disposal rate (eGDR) (NCT04664036) and by performing a hyperinsulinemic-euglycemic clamp (HEC) (NCT04623320). All glucometrics were calculated over 28 days. RESULTS: A total of 287 subjects were included. Mean age was 46 ± 17 years, 55% were male, TIR was 57% ± 14%, and eGDR was 7.6 (5.6-9.3) mg/kg/min. The tertile of people with the lowest eGDR (highest level of IR) had a higher TAR compared to the tertile with the highest eGDR (39% ± 15% vs 33% ± 14%, P = .043). Using logistic regression, a higher eGDR was associated with a higher chance to fall in a higher TIR-tertile (odds ratio [OR] 1.251, P < .001), a lower TAR-tertile (OR 1.281, P < .001), and a higher TBR-tertile (OR 0.893, P = .039), adjusted for age, sex, diabetes duration, smoking status, and alcohol intake. In the 48 people undergoing a HEC, no significant association between glucometrics and the HEC-determined glucose disposal rate (M-value) was observed. CONCLUSION: In people with T1D, an association between IR, measured by eGDR, and worse CGM profiles was observed.

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. METHODS: We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. IMPACT AND IMPLICATIONS: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

A cross-sectional analysis of the association between testosterone and biopsy-proven non-alcoholic fatty liver disease in men with obesity.

PURPOSE: To study the association between testosterone and non-alcoholic fatty liver disease (NAFLD) since prior studies have reported inconsistent results. METHODS: A retrospective analysis was performed including obese men who underwent a liver biopsy and a metabolic and hepatological work-up. Free testosterone (CFT) was calculated by the Vermeulen equation. The association between total testosterone (total T) and CFT on the one hand and NAFLD and fibrosis on the other hand was investigated and corrected for biasing factors such as metabolic parameters. RESULTS: In total, 134 men (mean age 45 ± 12 years, median BMI 39.6 (25.0-64.9) kg/m²) were included. The level of total T and CFT did not significantly differ between NAFL and NASH and the stages of steatosis and ballooning. CFT was significantly lower in a higher stage of fibrosis (p = 0.013), not seen for total T and not persisting after controlling for the influence of BMI, HDL cholesterol and HOMA-IR. A higher stage of lobular inflammation was associated with a lower level of total T (p = 0.033), not seen for CFT and not persisting after controlling for the influence of visceral adipose tissue surface and HOMA-IR. CONCLUSIONS: This is the second largest study investigating the association between testosterone and biopsy-proven NAFLD. No significant association between testosterone levels and NAFLD, and the different histological subgroups or fibrosis was seen. The lower level of CFT in a higher stage of fibrosis and the association between total T and lobular inflammation was driven by poor metabolic parameters.

Sex differences in diabetic foot ulcer severity and outcome in Belgium.

BACKGROUND: Sex differences are increasingly recognized to play an important role in the epidemiology, treatment and outcomes of many diseases. This study aims to describe differences between sexes in patient characteristics, ulcer severity and outcome after 6 months in individuals with a diabetic foot ulcer (DFU). METHODS: A total of 1,771 patients with moderate to severe DFU participated in a national prospective, multicenter cohort study. Data were collected on demographics, medical history, current DFU and outcome. For data analysis, a Generalized Estimating Equation model and an adjusted Cox proportional hazards regression were used. RESULTS: The vast majority of patients included were male (72%). Ulcers in men were deeper, more frequently displaying probe to bone, and more frequently deeply infected. Twice as many men presented with systemic infection as women. Men demonstrated a higher prevalence of previous lower limb revascularization, while women presented more frequently with renal insufficiency. Smoking was more common in men than in women. No differences in presentation delay were observed. In the Cox regression analysis, women had a 26% higher chance of healing without major amputation as a first event (hazard ratio 1.258 (95% confidence interval 1.048-1.509)). CONCLUSIONS: Men presented with more severe DFU than women, although no increase in presentation delay was observed. Moreover, female sex was significantly associated with a higher probability of ulcer healing as a first event. Among many possible contributing factors, a worse vascular state associated with a higher rate of (previous) smoking in men stands out.

Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism.

BACKGROUND: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. APPROACH AND RESULTS: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others. CONCLUSION: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide, and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms 'glucagon-like peptide-1 receptor agonist', 'glucagon receptor agonist', 'glucose-dependent insulinotropic peptide', 'dual or co-agonist', and 'tirzepatide'. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.

Non-Alcoholic Steatohepatitis Decreases Microsomal Liver Function in the Absence of Fibrosis.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice.

Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus.

BACKGROUND: Roux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG. METHODS: Eighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery. RESULTS: Postoperative fasting blood glucose decreased similarly in both groups (LRYGB vs. SG; baseline-8.1 ± 0.6 vs. 8.2 ± 0.4 mmol/l, 2 days-7.8 ± 0.5 vs. 7.4 ± 0.3 mmol/l, 3 weeks-6.6 ± 0.4 vs. 6.6 ± 0.3 mmol/l, respectively, P < 0.01 vs. baseline for both groups; 12 months-6.6 ± 0.4 vs. 5.9 ± 0.4, respectively, P < 0.05 for LRYGB and P < 0.001 for LSG vs. baseline, P = ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean ± SEM; LSG + 58 ± 14%, P < 0.01; LRYGB - 8 ± 17%, P = ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525 ± 1258 vs. 4779 ± 712 pmol × min, respectively, P < 0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (- 10.1 ± 0.9 vs. - 7.9 ± 0.5 kg/m2, respectively, P < 0.05). CONCLUSION: LRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG.

Bile Acid Alterations Are Associated With Insulin Resistance, but Not With NASH, in Obese Subjects.

Context: Bile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear. Objective: To assess BA alterations associated with NASH independently of body mass index and IR. Design and Setting: Patients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014. Patients: Obese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR. Main Outcome Measures: Transcriptomic analyses were performed on liver biopsies. Plasma concentrations of 21 BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography-tandem mass spectrometry. Plasma fibroblast growth factor 19 was measured by enzyme-linked immunosorbent assay. Results: Plasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors-farnesoid X, pregnane X, and vitamin D receptors-was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling. Conclusions: In obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation.

A Preliminary Link between Hydroxylated Metabolites of Polychlorinated Biphenyls and Free Thyroxin in Humans.

BACKGROUND: Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (HO-PCBs) interfere with thyroid hormone action both in vitro and in vivo. However, epidemiologic studies on the link between PCB exposure and thyroid function have yielded discordant results, while very few data are available for HO-PCBs. OBJECTIVES: Our study aimed at investigating the relationship between clinically available markers of thyroid metabolism and serum levels of both PCBs and HO-PCBs. SUBJECTS AND METHODS: In a group of 180 subjects, thyroid-stimulating hormone (TSH) and free thyroxin (fT4), 29 PCBs (expressed both in lipid weight and in wet weight) and 18 HO-PCBs were measured in serum. RESULTS: In regression models, adjusted for gender, age, current smoking behavior, BMI and total lipid levels, serum levels of 3HO-PCB118 and 3HO-PCB180, and PCB95(lw), PCB99(lw) and PCB149(lw) were independent, significant predictors of fT4. A stepwise, multiple regression with gender, age, current smoking behavior, BMI and total lipid levels and all five previously identified significant compounds retained age, BMI, PCB95(lw), PCB99(lw) and 3HO-PCB180 as significant predictors of fT4. TSH levels were not predicted by serum levels of any of the PCBs or HO-PCBs. CONCLUSIONS: Our study indicates that in vivo, circulating fT4 levels can be linked to serum levels of several PCBs and hydroxylated PCB metabolites.

Endocrine-disrupting polychlorinated biphenyls in metabolically healthy and unhealthy obese subjects before and after weight loss: difference at the start but not at the finish.

BACKGROUND: A subset of obese individuals does not exhibit metabolically unfavorable features; this group is referred to as metabolically healthy obese (MHO). Serum concentrations of polychlorinated biphenyls (PCBs), which are chemicals with endocrine-disrupting properties, have been shown to be lower in MHO than in metabolically unhealthy obese (MUO). OBJECTIVE: We studied PCB serum concentrations during and after weight loss and their relation with metabolic health. DESIGN: We determined metabolic health features (weight, blood pressure, lipids, inflammation, and glucose metabolism) and serum PCB concentrations of 27 PCBs in a cohort of 184 overweight and obese subjects. Metabolic health was evaluated with the use of the criteria of the metabolic syndrome (MetS) [metabolic syndrome according to Adult Treatment Panel III criteria present (MetS+) or metabolic syndrome according to Adult Treatment Panel III criteria absent (MetS−)] or with extended criteria with inflammation and insulin resistance taken into account (MUO compared with MHO). Participants were treated with lifestyle counseling or bariatric surgery. A metabolic and toxicological re-evaluation was performed after 6 and 12 mo. RESULTS: At baseline, serum ΣPCB concentrations were significantly higher in MUO than in MHO (ΣPCBs: 138 ±105 compared with 365 ± 481 ng/g lipid weight; P = 0.01) but not in MetS+ compared with MetS− subjects. No difference was detected in the percentage increase in PCB serum concentrations in MetS+ compared with MetS− subjects (median: 58% compared with 43% and 31% compared with 69% at 6 and 12 mo, respectively). The comparison of persistent with resolved MetS and MUO did not reveal any difference in ΣPCB concentration increments (median: 49% compared with 58% at 12 mo for MUO; P > 0.05). In a regression model with age, smoking, and body mass index corrected for, PCB serum concentrations at baseline were not predictive of the persistence or resolution of a metabolically unfavorable state. CONCLUSION: Our study indicates that the increment in serum concentrations of PCBs does not differ according to metabolic health and does not seem to influence the beneficial metabolic health effects of weight loss. This study was registered at clinicaltrials.gov at NCT01778868.

Urinary phthalate metabolites are associated with insulin resistance in obese subjects.

Phthalates are potentially involved in the development of type 2 diabetes mellitus. In a cohort of 123 obese subjects, 10 phthalate metabolites were analyzed. An oral glucose tolerance test was performed and various estimates of insulin resistance and beta-cell function were calculated. After adjustment for age, physical activity level, smoking behavior, medication use and body mass index, several phthalate metabolites were linked to markers of glucose tolerance and insulin resistance.

Daily intake of bisphenol A and triclosan and their association with anthropometric data, thyroid hormones and weight loss in overweight and obese individuals.

Bisphenol A (BPA) and triclosan (TCS) were determined in urine of Belgian overweight and obese (n=151) and lean (n=43) individuals. After the first urine collection (0M), obese patients started a diet program or have undergone bariatric surgery. Hereafter, three additional urine samples from obese patients were collected after 3 (3M), 6 (6M) and 12 (12M) months. Both compounds were detected in >99% of the samples. BPA had median concentrations of 1.7 and 1.2ng/mL in obese and lean groups, respectively, while TCS had median concentrations of 1.5 and 0.9ng/mL in the obese and lean groups, respectively. The obese group had higher urinary concentrations (ng/mL) of BPA (p<0.5), while no significant differences were found for TCS between the obese and lean groups. No time trends between the different collection moments were observed. The BPA concentrations in the obese group were negatively associated with age, while no gender difference or relationship with body mass index was observed. For TCS, no relationships with gender, BMI, or age were found. The temporal variability of BPA and TCS was assessed with calculation of the intraclass correlation coefficient, Spearman rank correlation coefficients, and surrogate category analysis. We observed evidence that single spot urine samples might be predictive of exposure over a longer period of time. Dietary intakes of BPA and TCS did not differ significantly among the time points considered after obese individuals started losing weight (6 and 12months). Multiple linear regression analyses after adjusting for age and weight loss revealed negative associations between urinary TCS and serum FT4 in the 0M and 3M female obese individuals and positive associations between urinary BPA and serum TSH in the lean group.

Exposure to persistent organic pollutants: relationship with abnormal glucose metabolism and visceral adiposity.

OBJECTIVE: The contribution of persistent organic pollutants (POPs) to the pandemic of type 2 diabetes mellitus and obesity has been assumed but remains speculative. Our study aimed at investigating the relationship of POP levels with detailed markers of glucose metabolism and body composition. RESEARCH DESIGN AND METHODS: Glucose tolerance was determined in a group of normal-weight and obese individuals. Fat distribution was assessed with abdominal computed tomography (CT) scanning, determining subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Selected POPs (28 polychlorinated biphenyls [PCBs] and the pesticide p,p'-dichlorodiphenyldichloroethylene [p,p'-DDE]) were measured in serum. In a subset of obese individuals undergoing bariatric surgery, POPs were also measured in adipose tissue. RESULTS: Among obese participants, serum and adipose tissue levels of POPs were significantly correlated to glucose levels during an oral glucose tolerance test. Logistic regression using a model including age, age(2), sex, family history of diabetes, BMI, CT-VAT, smoking behavior, physical activity level score, and a POP level identified serum levels of PCB153, the sum of PCBs and p,p'-DDE as significant predictors of abnormal glucose tolerance (odds ratio 4.6, 4.8, and 3.4, respectively; P < 0.05). Adipose tissue levels of p,p'-DDE were also significant predictors (odds ratio 81.6; P < 0.05). Serum levels of PCBs were inversely related to BMI, while serum and adipose tissue levels of all POPs were positively related to the CT-VAT/SAT ratio, suggesting an important role for the visceral fat compartment in POP dynamics. CONCLUSIONS: Our findings further sustain the theory that exposure to environmentally relevant levels of POPs may exert both a diabetogenic and obesogenic effect.

Expression of obesity markers and Persistent Organic Pollutants levels in adipose tissue of obese patients: reinforcing the obesogen hypothesis?

INTRODUCTION: Persistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity. OBJECTIVES: THE AIM IS TWOFOLD: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT. RESULTS AND CONCLUSIONS: Leptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the obesogen hypothesis.

Phthalate metabolites in obese individuals undergoing weight loss: Urinary levels and estimation of the phthalates daily intake.

Human exposure to chemicals commonly encountered in our environment, like phthalates, is routinely assessed through urinary measurement of their metabolites. A particular attention is given to the specific population groups, such as obese, for which the dietary intake of environmental chemicals is higher. To evaluate the exposure to phthalates, nine phthalate metabolites (PMs) were analyzed in urine collected from obese individuals and a control population. Obese individuals lost weight through either bariatric surgery or a conservative weight loss program with dietary and lifestyle counseling. Urine samples were also collected from the obese individuals after 3, 6 and 12months of weight loss. Individual daily intakes of the corresponding phthalate diesters were estimated based on the urinary PM concentrations. A high variability was recorded for the levels of each PM in both obese and control urine samples showing the exposure to high levels of PMs in specific subgroups. The most important PM metabolite as percentage contribution to the total PM levels was mono-ethyl phthalate followed by the metabolites of di-butyl phthalate and di 2-ethyl-hexyl phthalate (DEHP). No differences in the PM levels and profiles between obese entering the program and controls were observed. Although paralleled by a significant decrease of their weight, an increase in the urinary PM levels after 3 to 6months loss was seen. Constant figures for the estimated phthalates daily intake were observed over the studied period, suggesting that besides food consumption, other human exposure sources to phthalates (e.g. air, dust) might be also important. The weight loss treatment method followed by obese individuals influenced the correlations between PM levels, suggesting a change of the intake sources with time. Except for few gender differences recorded between the urinary DEHP metabolites correlations, no other differences were observed for the urinary PM levels as a function of age, body mass index or waist circumference. Linear regression analysis showed almost no significance of the relationship between measured urinary PMs and serum free thyroxine, thyroid-stimulating hormone (TSH) for all obese individuals participating to the study, while for the control samples, several PMs were significantly associated with the serum TSH levels.

Obesity and persistent organic pollutants: possible obesogenic effect of organochlorine pesticides and polychlorinated biphenyls.

Persistent organic pollutants (POPs) are endocrine-disrupting chemicals associated with the development of the metabolic syndrome and type 2 diabetes. In humans, little is known about their role in the potential origin of obesity. This study aims to assess the associations between serum levels of POPs and the prevalence of obesity in a cohort of obese and lean adult men and women. POP serum samples were investigated cross-sectionally in 98 obese and 47 lean participants, aged ≥18 years. Serum samples were analyzed for the presence of polychlorinated biphenyl (PCB) congeners 153, 138, 180, and 170 and for the organochlorine pesticides, dichloro-diphenyl-dichloroethylene (pp-DDE), and ß-hexachlorocyclohexane (ßHCH). We established a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissue, and serum levels of PCB 153, 180, 170, and the sumPCBs. For ßHCH, we demonstrated a positive correlation with BMI, waist, fat mass percentage, and total and subcutaneous abdominal adipose tissue. PCBs 180, 170, and the sum of PCBs correlated significantly negative with homeostasis model assessment for insulin resistance (HOMA(IR)). ßHCH correlated significantly positively with HOMA(IR). A strong correlation was established between all POP serum levels and age. We established a positive relationship between high serum levels of ßHCH and BMI and HOMA(IR), whereas serum PCB levels were inversely correlated with BMI and HOMA(IR). Combined, these results suggest that the diabetogenic effect of low-dose exposure to POPs might be more complicated than a simple obesogenic effect.