BackgroundThe 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.ObjectiveWe investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders.MethodsSprague-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.ResultsAdult 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.ConclusionOur findings provide evidence that exposure to POPs commonly present in food chains leads to insulin resistance and associated metabolic disorders.

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes.

BackgroundThe uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis.Methodology/Principal FindingsHere we report that cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed β-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE2 receptor antagonists implicated EP4 as a main PGE2 receptor, and injection of the stable PGE2 analog (EP3/4 agonist) 16,16 dm PGE2 induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality.Conclusions/SignificanceOur findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.

Brown adipose tissue (BAT) is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine BAT thermogenic capacity prior to environmental cold are unknown. Here we show that Histone Deacetylase 3 (HDAC3) is required to activate BAT enhancers to ensure thermogenic aptitude. Mice with BAT-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is also marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of Estrogen-Related Receptor α (ERRα) in BAT. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Pgc-1α and OXPHOS genes. Importantly, HDAC3 promotes the basal transcription of these genes independent of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged upon exposure to dangerously cold temperature.