Jérôme Ruzzin

Persistent organic pollutant exposure leads to insulin resistance syndrome.

Background The incidence of the insulin resistance syndrome has increased at an alarming rate worldwide, creating a serious challenge to public health care in the 21st century. Recently, epidemiological studies have associated the prevalence of type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. Objective We investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders. Methods Sprague-Dawley rats were exposed for 28 days to lipophilic POPs through the consumption of a high-fat diet containing either refined or crude fish oil obtained from farmed Atlantic salmon. In addition, differentiated adipocytes were exposed to several POP mixtures that mimicked the relative abundance of organic pollutants present in crude salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, and gene expression and we performed microarray analysis. Results Adult male rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity, and hepatosteatosis. The contribution of POPs to insulin resistance was confirmed in cultured adipocytes where POPs, especially organochlorine pesticides, led to robust inhibition of insulin action. Moreover, POPs induced down-regulation of insulin-induced gene-1 (Insig-1) and Lpin1, two master regulators of lipid homeostasis. Conclusion Our findings provide evidence that exposure to POPs commonly present in food chains leads to insulin resistance and associated metabolic disorders.

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.

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.

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.

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.

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

BackgroundPersistent 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.DiscussionThere 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.SummaryThe 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.

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 β-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.

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.

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 secret story of fish: decreasing nutritional value due to pollution?

Fish, especially fatty fish, have long been viewed as a healthy dietary component because of their unique content of longchain n-3 PUFA (n-3 fatty acids). An observation in 852 male residents of Zutphen, The Netherlands, aged 40–59 years in 1960 indicated that fish intake was inversely associated with the incidence of CHD over 20 years of follow-up. On the other hand, fish may also contain diverse environmental pollutants such as heavy metals and persistent organic pollutants (POP), including organochlorine pesticides, polychlorinated biphenyls (PCB), dioxins, polybrominated diphenylether (PBDE) and perfluorinated compounds (PFCO). Therefore, different studies evaluating potential risks v. benefits of fish consumption, especially with respect to CVD, have been performed. Although various results have been reported, it has generally been suggested that the benefits of fish eating outweigh the risks. Compared with CVD, the situation for diabetes has remained largely unexplored. Recently, several prospective studies have documented that the consumption of fish was associated with a higher later occurrence of type 2 diabetes, a disease strongly linked to heart disease and stroke, yet that has a much distinct pathophysiology linked to glucose dysregulation and microvascular deterioration. In this issue of the British Journal of Nutrition, a meta-analysis performed by Zhou et al. summarises these and other studies, concluding that fish and n-3 fatty acid consumption is associated with a significantly increased risk of type 2 diabetes. In two other meta-analyses of the same topic and of largely the same data, it has been concluded that there was no benefit from fish intake in terms of reduced diabetes risk. How can we explain these findings? Have the health effects associated with fish consumption been overestimated? At an experimental level, several pieces of evidence support the idea that the health effects of fish consumption vary depending on the presence or absence of POP. Rats exposed to contaminated salmon oil (containing background levels of POP) developed metabolic complications linked to type 2 diabetes, whereas animals exposed to decontaminated salmon oil (treated to achieve very low levels of POP) did not show such disturbances. Furthermore, mice fed commercially available farmed salmon fillet with common POP levels were found to develop insulin resistance, glucose intolerance, visceral obesity, fatty liver and chronic low-grade inflammation, in contrast to mice fed farmed salmon fillet containing lower levels of POP, which showed a better metabolic profile. In addition, consumption of salmon protein hydrolysate containing less than 0·2 % of lipids, and therefore very low concentrations of POP, was found to protect rats against insulin resistance induced by a high-fat diet containing lard and ‘corn oil’. Taken together, these findings emphasise that background levels of POP, which many people consider to be at safe levels, can completely counteract the potential benefits of n-3 fatty acids and other nutrients present in fish, in particular leading to the serious metabolic features which often precede type 2 diabetes. Thus, these animal feeding studies are consistent with the recent human prospective and cross-sectional studies showing an association between type 2 diabetes and POP. Previously, Kaushik et al. reported that, whereas fish and n-3 fatty acid intake increases the risk of diabetes, the consumption of n-3 fatty acid supplements did not. Interestingly, the oil found in most n-3 fatty acid supplements differs considerably from the oil found in fatty fish, in that most lipophilic pollutants such as POP have been extracted through decontamination processes. On the other hand, the oil present in fatty fish has not been decontaminated, and often contains many POP because these pollutants are omnipresent in aquatic environments, making fatty fish one of the most important sources of human exposure to POP. Furthermore, the presence of POP in fish, compared with other food products, is still poorly regulated. In the European Union, the levels of organochlorine pesticides, PCB and PBDE in fish and seafood are, for instance, still unregulated. Thus, the exposure to POP through fatty fish intake could have contributed to an enhanced risk of diabetes. These findings also pinpoint that the common practice to extrapolate the results obtained with n-3-derived supplements to fatty fish, or seafood in general, has probably led to a serious misinterpretation and should be done with extreme caution. The concentrations and types of POP mixtures may vary substantially in fatty fish depending on the food consumed, the time and the geographic area of the fish. Similarly, although n-3-derived supplements may contain lower levels of POP than fatty fish, the levels of POP in these supplements may fluctuate considerably due to differing methods used by the industry to refine the oil, including activated carbon adsorption, short-path distillation and deodorisation. This varying quality of fish and n-3-derived supplements has probably contributed to the different findings about the British Journal of Nutrition (2012), 108, 397–399 doi:10.1017/S0007114512002048 q The Authors 2012