Mice lacking intestinal Nr1i2 have normal intestinal homeostasis under steady-state conditions and are not hypersensitive to inflammation under lipopolysaccharide treatment.

Nr1i2, a nuclear receptor known for its key function in xenobiotic detoxification, has emerged as a potential regulator of intestinal homeostasis and inflammation. However, the role of Nr1i2 in different intestinal segments remains poorly known. Moreover, in vivo investigations on intestinal Nr1i2 have essentially been performed in whole-body Nr1i2 knockout (Nr1i2-/- ) mice where the deletion of Nr1i2 in all tissues may affect the intestinal phenotype. To better understand the role of Nr1i2 in the intestine, we generated intestinal epithelial-specific Nr1i2 knockout (iNr1i2-/- ) mice and studied the duodenum, jejunum, ileum, and colon of these animals during steady-state conditions and lipopolysaccharide (LPS)-induced inflammation. As compared to control (iNr1i2+/+ ) mice, iNr1i2-/- mice showed normal intestinal permeability as assessed by in vivo FITC-dextran test. The expression of genes involved in inflammation, tight- and adherens-junction, proliferation, glucose, and lipid metabolism was comparable in the duodenum, jejunum, ileum, and colon of iNr1i2-/- and iNr1i2+/+ mice. In line with these findings, histological analyses of the jejunum revealed no difference between iNr1i2-/- and iNr1i2+/+ mice. When treated with LPS, the intestine of iNr1i2-/- mice had no increased inflammatory response as compared to iNr1i2+/+ mice. Moreover, the health monitoring of LPS-treated iNr1i2-/- and iNr1i2+/+ mice was similar. Taken together, our results demonstrate that the specific deletion of Nr1i2 in the intestinal epithelium does not cause major intestinal damages in mice during both steady-state and inflammatory conditions.

Effect of fatty fish or nut consumption on concentrations of persistent organic pollutants in overweight or obese men and women: A randomized controlled clinical trial.

BACKGROUND AND AIMS: While excess energy intake and physical inactivity constitute the obvious causes of body fat accumulation, persistent organic pollutants (POPs) are novel factors that have been linked to cardiometabolic disorders. Major sources of POPs are animal fats including fatty fish. Given the putative protective effects of fish on cardiovascular disease, we explored whether high consumption of fatty fish increased serum concentrations of POPs. METHODS AND RESULTS: Men and women aged 35-70 years with body mass index between 25 and 38 kg/m2 and at least 1 cardiometabolic component were randomized to high intakes of fatty fish (mostly farmed salmon, ∼630 g/week; n = 45), high intakes of nuts (∼200 g/week; n = 42) or a control group following their usual diet but restricting fatty fish and nuts for 6 months (n = 44). Concentrations of 15 POPs (5 organochlorinated compounds, 2 dioxin-like polychlorinated biphenyls and 8 non-dioxin-like polychlorinated biphenyls) and cardiometabolic risk factors were measured at baseline and end of the study. Results showed that changes in concentrations of individual and classes of POPs did not differ between the dietary groups and controls (p > 0.05). Among cardiometabolic risk factors HDL-cholesterol increased in the fatty fish group compared to controls (+0.10 mmol/L, CI (0.05-0.20); p = 0.005) while no changes were observed in the group consuming nuts. CONCLUSION: Fatty fish consumption for 6 months did not increase the serum concentrations of POPs in individuals with overweight or obesity and metabolic risk. While this finding appears reassuring regarding short-term intakes of farmed salmon, long term variations in POPs in adipose stores require further study.

Correction to: Parma consensus statement on metabolic disruptors.

CORRECTION: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Parma consensus statement on metabolic disruptors.

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Persistent organic pollutants disrupt the oxidant/antioxidant balance of INS-1E pancreatic ß-cells causing their physiological dysfunctions.

BACKGROUND: Persistent organic pollutants (POPs) have emerged as potent diabetogenic agents, but their mechanisms of action remain poorly identified. OBJECTIVES: In this study, we aim to determine the mechanisms regulating the damaging effects of POPs in pancreatic ß-cells, which have a central role in the development of diabetes. METHODS: We treated INS-1E pancreatic ß-cells with PCB-153, p,p'-DDE, PCB-126, or TCDD at doses ranging from 1 × 10-15to 5 × 10-6M. We measured insulin content and secretion, cell viability and assessed the mRNA expression of the xenobiotic nuclear receptors Nr1i2 and Nr1i3, and the aryl hydrocarbon receptor (Ahr). In addition, we evaluated the antioxidant defense and production of reactive oxygen species (ROS). Finally, we studied the ability of the antioxidant N-acetyl-L-cysteine (NAC) to counteract the effects of POPs in INS-1E cells. RESULTS: When exposed to environmental POP levels, INS-1E cells had impaired production and secretion of insulin. These defects were observed for all tested POPs and were paralleled by reduced Ins1 and Ins2 mRNA expression. While POP treatment for 3 days did not affect INS-1E cell viability, longer treatment progressively killed the cells. Furthermore, we found that the xenobiotic detoxification machinery is poorly expressed in the INS-1E cells, as characterized by the absence of Nr1i2 and Nr1i3 and their respective downstream targets Cyp3a1/Cyp3a2 and Cyp2b1/Cyp2b3, and the weak functionality of the Ahr/Cyp1a1 signaling. Interestingly, POPs dysregulated key antioxidant enzymes such as glutathione peroxidases, peroxiredoxins, thioredoxins, and catalases. In parallel, the production of intracellular ROS, including superoxide anion (O2•-) and hydrogen peroxide (H2O2), was increased by POP exposure. Improving the oxidant scavenging capacity of INS-1E cells by NAC treatment restored the production and secretion of insulin. CONCLUSION: By promoting oxidative stress and impairing the ability of INS-1E cells to produce and secrete insulin, this study reveals how POPs can mechanistically act as diabetogenic agents, and provides new scientific evidence supporting the concept that POPs are fueling the diabetes epidemics.

Treatment with fibroblast growth factor 19 increases skeletal muscle fiber size, ameliorates metabolic perturbations and hepatic inflammation in 5/6 nephrectomized mice.

Chronic kidney disease (CKD) is associated with osteosarcopenia, and because a physical decline in patients correlates with an increased risk of morbidity, an improvement of the musculoskeletal system is expected to improve morbi-mortality. We recently uncovered that the intestinal hormone Fibroblast Growth Factor 19 (FGF19) is able to promote skeletal muscle mass and strength in rodent models, in addition to its capacity to improve glucose homeostasis. Here, we tested the effects of a treatment with recombinant human FGF19 in a CKD mouse model, which associates sarcopenia and metabolic disorders. In 5/6 nephrectomized (5/6Nx) mice, subcutaneous FGF19 injection (0.1 mg/kg) during 18 days increased skeletal muscle fiber size independently of food intake and weight gain, associated with decreased gene expression of myostatin. Furthermore, FGF19 treatment attenuated glucose intolerance and reduced hepatic expression of gluconeogenic genes in uremic mice. Importantly, the treatment also decreased gene expression of liver inflammatory markers in CKD mice. Therefore, our results suggest that FGF19 may represent a novel interesting therapeutic strategy for a global improvement of sarcopenia and metabolic complications in CKD.

Public health concern behind the exposure to persistent organic pollutants and the risk of metabolic diseases.

BACKGROUND: Persistent organic pollutants (POPs) are hazardous chemicals omnipresent in our food chain, which have been internationally regulated to ensure public health. Initially described for their potency to affect reproduction and promote cancer, recent studies have highlighted an unexpected implication of POPs in the development of metabolic diseases like type 2 diabetes and obesity. Based on this novel knowledge, this article aims at stimulating discussion and evaluating the effectiveness of current POP legislation to protect humans against the risk of metabolic diseases. Furthermore, the regulation of POPs in animal food products in the European Union (EU) is addressed, with a special focus on marine food since it may represent a major source of POP exposure to humans. DISCUSSION: There is mounting scientific evidence showing that current POP risk assessment and regulation cannot effectively protect humans against metabolic disorders. Better regulatory control of POPs in dietary products should be of high public health priority. SUMMARY: The general population is exposed to sufficient POPs, both in term of concentration and diversity, to induce metabolic disorders. This situation should attract the greatest attention from the public health and governmental authorities.

Associations between persistent organic pollutants and type 1 diabetes in youth.

BACKGROUND: Diabetes affects millions of people worldwide with a continued increase in incidence occurring within the pediatric population. The potential contribution of persistent organic pollutants (POPs) to diabetes in youth remains poorly known, especially regarding type 1 diabetes (T1D), generally the most prevalent form of diabetes in youth. OBJECTIVES: We investigated the associations between POPs and T1D in youth and studied the impacts of POPs on pancreatic ß-cell function and viability in vitro. METHODS: We used data and plasma samples from the SEARCH for Diabetes in Youth Case Control Study (SEARCH-CC). Participants were categorized as Controls, T1D with normal insulin sensitivity (T1D/IS), and T1D with insulin resistance (T1D/IR). We assessed plasma concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides and estimated the odds of T1D through multivariable logistic regression. In addition, we performed in vitro experiments with the INS-1E pancreatic ß-cells. Cells were treated with PCB-153 or p,p'-DDE at environmentally relevant doses. We measured insulin production and secretion and assessed the mRNA expression of key regulators involved in insulin synthesis (Ins1, Ins2, Pdx1, Mafa, Pcsk1/3, and Pcsk2), glucose sensing (Slc2a2 and Gck), and insulin secretion (Abcc8, Kcnj11, Cacna1d, Cacna1b, Stx1a, Snap25, and Sytl4). Finally, we assessed the effects of PCB-153 and p,p'-DDE on ß-cell viability. RESULTS: Among 442 youths, 112 were controls, 182 were classified with T1D/IS and 148 with T1D/IR. The odds ratios (OR) of T1D/IS versus controls were statistically significant for p,p'-DDE (OR 2.0, 95% confidence interval (CI) 1.0, 3.8 and 2.4, 95% CI 1.2, 5.0 for 2nd and 3rd tertiles, respectively), trans-nonachlor (OR 2.5, 95% CI 1.3, 5.0 and OR 2.3, 95% CI 1.1, 5.1 for 2nd and 3rd tertiles, respectively), and PCB-153 (OR 2.3, 95% CI 1.1, 4.6 for 3rd tertile). However, these associations were not observed in participants with T1D/IR. At an experimental level, treatment with p,p'-DDE or PCB-153, at concentrations ranging from 1 × 10-15 M to 5 × 10-6 M, impaired the ability of pancreatic ß-cells to produce and secrete insulin in response to glucose. These failures were paralleled by impaired Ins1 and Ins2 mRNA expression. In addition, among different targeted genes, PCB-153 significantly reduced Slc2a2 and Gck mRNA expression whereas p,p'-DDE mainly affected Abcc8 and Kcnj11. While treatment with PCB-153 or p,p'-DDE for 2 days did not affect ß-cell viability, longer treatment progressively killed the ß-cells. CONCLUSION: These results support a potential role of POPs in T1D etiology and demonstrate a high sensitivity of pancreatic ß-cells to POPs.

Fibroblast growth factor 19 as a countermeasure to muscle and locomotion dysfunctions in experimental cerebral palsy.

BACKGROUND: Cerebral palsy (CP) associates cerebral function damages with strong locomotor defects and premature sarcopenia. We previously showed that fibroblast growth factor 19 (FGF19) exerts hypertrophic effects on skeletal muscle and improves muscle mass and strength in mouse models with muscle atrophy. Facing the lack of therapeutics to treat locomotor dysfunctions in CP, we investigated whether FGF19 treatment could have beneficial effects in an experimental rat model of CP. METHODS: Cerebral palsy was induced in male Wistar rat pups by perinatal anoxia immediately after birth and by sensorimotor restriction of hind paws maintained until Day 28. Daily subcutaneous injections with recombinant human FGF19 (0.1 mg/kg bw) were performed from Days 22 to 28. Locomotor activity and muscle strength were assessed before and after FGF19 treatment. At Day 29, motor coordination on rotarod and various musculoskeletal parameters (weight of tibia bone and of soleus and extensor digitorum longus (EDL) muscles; area of skeletal muscle fibres) were evaluated. In addition, expression of specific genes linked to human CP was measured in rat skeletal muscles. RESULTS: Compared to controls, CP rats had reduced locomotion activity (-37.8% of distance travelled, P < 0.05), motor coordination (-88.9% latency of falls on rotarod, P < 0.05) and muscle strength (-25.1%, P < 0.05). These defects were associated with reduction in soleus (-51.5%, P < 0.05) and EDL (-42.5%, P < 0.05) weight, smaller area of muscle fibres, and with lower tibia weight (-38%, P < 0.05). In muscles from rats submitted to CP, changes in the expression levels of several genes related to muscle development and neuromuscular junctions were similar to those found in wrist muscle of children with CP (increased mRNA levels of Igfbp5, Kcnn3, Gdf8, and MyH4 and decreased expression of Myog, Ucp2 and Lpl). Compared with vehicle-treated CP rats, FGF19 administration improved locomotor activity (+53.2%, P < 0.05) and muscle strength (+25.7%, P < 0.05), and increased tibia weight (+13.8%, P < 0.05) and soleus and EDL muscle weight (+28.6% and +27.3%, respectively, P < 0.05). In addition, it reduced a number of very small fibres in both muscles (P < 0.05). Finally, gene expression analyses revealed that FGF19 might counteract the immature state of skeletal muscles induced by CP. CONCLUSIONS: These results demonstrate that pharmacological intervention with recombinant FGF19 could restore musculoskeletal and locomotor dysfunction in an experimental CP model, suggesting that FGF19 may represent a potential therapeutic strategy to combat the locomotor disorders associated with CP.

Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice.

The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of ß-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting.

Adrenaline potentiates insulin-stimulated PKB activation via cAMP and Epac: implications for cross talk between insulin and adrenaline.

Adrenaline and insulin are two of the most important hormones regulating a number of physiological processes in skeletal muscle. Insulin's effects are generally requiring PKB and adrenaline effects cAMP and PKA. Recent evidence indicates cAMP can regulate PKB in some cell types via Epac (Exchange protein directly activated by cAMP). This suggests possible crossover between insulin and adrenaline signalling in muscle. Here we find that adrenaline alone did not influence PKB activation, but adrenaline dramatically potentiated insulin-stimulated phosphorylation of PKB (both Ser473 and Thr308) and of PKBalpha and PKBbeta enzyme activities. These effects were inhibited by wortmannin but adrenaline did not increase insulin-stimulated p85alpha PI 3-kinase activity. Adrenaline effects occurred via beta-adrenergic receptors and accumulation of cAMP. Interestingly, the Epac specific cAMP analogue 8-(4-chlorophenylthio)-2'-O-methyl-cAMP potentiated insulin-stimulated PKB phosphorylation in a similar manner as adrenaline did without activating glycogen phosphorylase. Inhibition of PKA by H89 decreased adrenaline-stimulated glycogen phosphorylase activation but increased PKB activation, which further supports that adrenaline increases insulin-stimulated PKB phosphorylation via Epac. Further, while adrenaline and the Epac activator alone did not promote p70(S6K) Thr389 phosphorylation, they potentiated insulin effects. In conclusion, adrenaline potentiates insulin-stimulated activation of PKB and p70(S6K) via cAMP and Epac in skeletal muscle. Furthermore, the fact that adrenaline alone did not activate PKB or p70(S6K) suggests that a hormone can be a potent regulator of signalling despite no effects being seen when co-activators are lacking.

Gas chromatography/atmospheric pressure chemical ionization/mass spectrometry for the analysis of organochlorine pesticides and polychlorinated biphenyls in human serum.

A method using a novel atmospheric pressure chemical ionization source for coupling gas chromatography (GC/APCI) to triple quadrupole mass spectrometry (MS/MS) for the determination of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) regulated by the Stockholm Convention is presented. One microliter injection of a six-point calibration curve of native PCBs and OCPs, ranging from 0.04 to 300pg/µL, was performed. The relative standard deviation (RSD) of the relative response factors (RRFs) was less than 15% with a coefficient of determination (r(2))>0.995. Meanwhile, two calibration solutions (CS), CS 2 (0.4pg/µL) and CS 3 (4pg/µL) were analyzed to study the repeatability calculated for both area and RRFs. The RSD for RRF ranged from 3.1 to 16% and 3.6 to 5.5% for CS 2 and CS 3, respectively. The limits of detection (LOD) determined by peak-to-peak signal-to-noise ratio (S/N) of 3 were compared between the GC/APCI/MS/MS and a GC coupled to high resolution mass spectrometry (GC/HRMS) system. GC/APCI/MS/MS resulted in lower LOD for most of the compounds, except for PCB#74, cis-chlordane and trans-chlordane. GC/APCI/MS/MS and GC/HRMS were also compared by performing analysis on 75 human serum samples together with eight QA/QC serum samples. The comparison between GC/APCI/MS/MS system and GC/HRMS system for 16 of the targeted compounds was carried out. No statistically significant difference was discovered. Due to increased sensitivity and user friendly operation under atmospheric pressure, GC/APCI/MS/MS is a powerful alternative technique that can easily meet the specification of GC/HRMS.

The metabolically healthy but obese phenotype is associated with lower plasma levels of persistent organic pollutants as compared to the metabolically abnormal obese phenotype.

CONTEXT: Although obesity is strongly linked to insulin resistance and type 2 diabetes, a subset of obese individuals termed metabolically healthy but obese (MHO) appears relatively protected from the development of cardiometabolic complications. The origins of this metabolically healthy phenotype remain unclear. Recently, persistent organic pollutants (POPs) have emerged as potential endocrine disruptors. OBJECTIVE: The aim of this study was to test the hypothesis that the MHO phenotype presents lower circulating levels of POPs as compared to the metabolically abnormal obese (MAO) phenotype. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of 76 nondiabetic obese (body mass index ≥30 kg/m(2)) postmenopausal women. MAIN OUTCOME MEASURES: Plasma concentrations of 21 POPs as well as cardiometabolic risk factors were analyzed. RESULTS: For similar age, body mass index, and fat mass index, MHO women (n = 40) showed higher insulin sensitivity levels and a more favorable cardiometabolic profile than MAO women (n = 36), as evidenced by a 2-fold increase in glucose disposal rates measured by the hyperinsulinemic-euglycemic clamp (P = .001). Among 18 detectable pollutants measured, MAO women had higher plasma concentrations of 12 POPs (fold increase, 1.4-2.9; P < .001-.036). Logistic regression analyses showed that the prevalence of the MAO phenotype was significantly associated with higher levels of total dioxin- and non-dioxin-like polychlorinated biphenyls (odds ratio, 4.7; 95% confidence interval, 1.8-12.5; P = .002), as well as trans-nonachlor (odds ratio, 6.1; 95% CI, 2.2-16.4; P < .001). CONCLUSION: Our study demonstrates that the metabolically healthy and abnormal phenotypes have distinct plasma POP profiles.

Metabolic impacts of high dietary exposure to persistent organic pollutants in mice.

Persistent organic pollutants (POPs) have been linked to metabolic diseases. Yet, the effects of high exposure to dietary POPs remain unclear. We therefore investigated whether elevated exposure to POPs provided by whale meat supplementation could contribute to insulin resistance. C57BL/6J mice were fed control (C) or very high-fat diet (VHF) containing low or high levels of POPs (VHF(+POPs)) for eight weeks. To elevate the dietary concentrations of POPs, casein was replaced by whale meat containing high levels of pollutants. Feeding VHF(+POPs) induced high POP accumulation in the adipose tissue of mice. However, compared with VHF-fed mice, animals fed VHF(+POPs) had improved insulin sensitivity and glucose tolerance, and reduced body weight. Levels of ectopic fat in skeletal muscles and liver were reduced in mice fed VHF(+POPs). These mice also gained less adipose tissue and had a tendency to reduced energy intake. In pair-feeding experiments, improved insulin action and reduced body weight gain were still observed in VHF(+POPs) compared to VHF pair-fed mice. We concluded that mice fed VHF contaminated with POPs derived from whale meat remain sensitive to insulin and glucose tolerant despite significant body burden of POPs. This indicates complex interactions between organic pollutants and nutrition in the development of metabolic disorders.

Differential effects of various fish proteins in altering body weight, adiposity, inflammatory status, and insulin sensitivity in high-fat-fed rats.

Mounting evidence suggests that the benefits of fish consumption are not limited to the well-appreciated effects of omega-3 fatty acids. We previously demonstrated that cod protein protects against the development of diet-induced insulin resistance. The goal of this study was to determine whether other fish protein sources present similar beneficial effects. Rats were fed a high-fat, high-sucrose diet containing protein from casein or fish proteins from bonito, herring, mackerel, or salmon. After 28 days, oral glucose tolerance tests or hyperinsulinemic-euglycemic clamps were performed; and tissues and plasma were harvested for biochemical analyses. Despite equal energy intake among all groups, the salmon-protein-fed group presented significantly lower weight gain that was associated with reduced fat accrual in epididymal white adipose tissue. Although this reduction in visceral adiposity was not associated with improved glucose tolerance, we found that whole-body insulin sensitivity for glucose metabolism was improved using the very sensitive hyperinsulinemic-euglycemic clamp technique. Importantly, expression of both tumor necrosis factor-α and interleukin-6 was reduced in visceral adipose tissue of all fish-protein-fed groups when compared with the casein-fed control group, suggesting that fish proteins carry anti-inflammatory properties that may protect against obesity-linked metabolic complications. Interestingly, consumption of the salmon protein diet was also found to raise circulating salmon calcitonin levels, which may underlie the reduction of weight gain in these rats. These data suggest that not all fish protein sources exert the same beneficial properties on the metabolic syndrome, although anti-inflammatory actions appear to be common.

Chronic consumption of farmed salmon containing persistent organic pollutants causes insulin resistance and obesity in mice.

BACKGROUND: Dietary interventions are critical in the prevention of metabolic diseases. Yet, the effects of fatty fish consumption on type 2 diabetes remain unclear. The aim of this study was to investigate whether a diet containing farmed salmon prevents or contributes to insulin resistance in mice. METHODOLOGY/PRINCIPAL FINDINGS: Adult male C57BL/6J mice were fed control diet (C), a very high-fat diet without or with farmed Atlantic salmon fillet (VHF and VHF/S, respectively), and Western diet without or with farmed Atlantic salmon fillet (WD and WD/S, respectively). Other mice were fed VHF containing farmed salmon fillet with reduced concentrations of persistent organic pollutants (VHF/S(-POPs)). We assessed body weight gain, fat mass, insulin sensitivity, glucose tolerance, ex vivo muscle glucose uptake, performed histology and immunohistochemistry analysis, and investigated gene and protein expression. In comparison with animals fed VHF and WD, consumption of both VHF/S and WD/S exaggerated insulin resistance, visceral obesity, and glucose intolerance. In addition, the ability of insulin to stimulate Akt phosphorylation and muscle glucose uptake was impaired in mice fed farmed salmon. Relative to VHF/S-fed mice, animals fed VHF/S(-POPs) had less body burdens of POPs, accumulated less visceral fat, and had reduced mRNA levels of TNFα as well as macrophage infiltration in adipose tissue. VHF/S(-POPs)-fed mice further exhibited better insulin sensitivity and glucose tolerance than mice fed VHF/S. CONCLUSIONS/SIGNIFICANCE: Our data indicate that intake of farmed salmon fillet contributes to several metabolic disorders linked to type 2 diabetes and obesity, and suggest a role of POPs in these deleterious effects. Overall, these findings may participate to improve nutritional strategies for the prevention and therapy of insulin resistance.