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Persistent organic pollutants (POPs) affect human health through the aryl hydrocarbon receptor (AhR) pathway and are implicated in mitochondrial dysfunction. Using data from the PIVUS study, we investigated the associations of serum AhR ligand (POP)-mediated luciferase activity (AhRL), mitochondrial ATP production inhibiting substances (MIS-ATP), and those affecting reactive oxygen species (MIS-ROS) with several metabolic syndrome (MetS) and cardiopulmonary function parameters. These include insulin resistance (HOMA-IR), inflammation, oxidative stress, and cardiopulmonary variables (FVC, FEV1, LV-EF, CCA distensibility). MIS-ATP showed significant correlations with HOMA-IR and pulmonary functions, indicating its direct impact of MIS-ATP on metabolic and pulmonary health. MIS-ROS correlated with oxidative stress markers and CCA distensibility, suggesting a role in systemic inflammatory responses. This study highlights the intricate relationships between environmental pollutant mixture and cardiopulmonary health in MetS as indicated by biomarkers of POP exposure in the elderly population, suggesting POP exposure may influence MetS onset and progression through mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Summary: From the lectures presented at the 2nd International Workshop on Obesity and Environmental Contaminants, which was held in Uppsala, Sweden, on 8–9 October 2015, it became evident that the findings from numerous animal and epidemiological studies are consistent with the hypothesis that environmental contaminants could contribute to the global obesity epidemic. To increase awareness of this important issue among scientists, regulatory agencies, politicians, chemical industry management, and the general public, the authors summarize compelling scientific evidence that supports the hypothesis and discuss actions that could restrict the possible harmful effects of environmental contaminants on obesity.

Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-[kappa]B ligand in cooperation with macrophage colony-stimulating factor (1-3). Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from [Ck.sup.-/-] mice were similarly affected. In vivo studies showed that [Ck.sup.-/-] mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development., Osteoclasts are key players in physiological bone remodeling, as well as in pathological conditions such as osteoporosis (1-3). Bone resorption involves the 'sealing-off' of isolated areas underneath active osteoclasts, a [...]

Both mitochondrial dysfunction and alterations in mitochondrial DNA (mtDNA) are implicated in type 2 diabetes mellitus and insulin resistance. Evidence also suggests that metabolism of S-adenosyl-L-methionine (SAM), the universal methyl donor for biological methylation, is associated with mitochondrial dysfunction and insulin resistance. We investigated the effect of SAM on mtDNA density and insulin sensitivity using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of type 2 diabetes mellitus and insulin resistance. To determine the short-term effect on mtDNA density, SAM (15 mg * [kg.sup.-1] * [d.sup.-1]) was administered intraperitoneally for 7 d to 6 male, 57-wk-old OLETF rats and 6 Long-Evans Tokushima Otsuka (LETO) rats of the same age as a nondiabetic control. To determine the long-term effect, the same dose of SAM was administered daily to 5 male, 6-wk-old OLETF rats until the age of 25 wk; 7 control OLETF rats received vehicle and 7 LETO rats were untreated. Skeletal muscle mtDNA density was measured by either competitive or multiplex PCR and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. SAM treatment for 1 wk increased skeletal muscle mtDNA density of both OLETF and LETO rats. The long-term SAM treatment significantly reduced body weight gain as well as increased skeletal muscle mtDNA density and whole body insulin sensitivity in OLETF rats compared with their vehicle-treated controls. Furthermore, in all 3 groups, skeletal muscle mtDNA density correlated with insulin sensitivity (r = 0.752, P < 0.001). In conclusion, SAM treatment increased mtDNA density in the skeletal muscle, improved whole body insulin sensitivity, and prevented body weight gain in OLETF rats.

Epidemiologic data suggest a strong association between low birth weight and increased risk of metabolic syndrome in adult life. However, the underlying mechanisms are largely unknown. To test the hypothesis that mitochondrial changes may serve as a link between poor nutrition in early life and insulin resistance in later life,we investigated the effect of protein malnutrition during gestation and lactation on mitochondria of the liver and skeletal muscle. Female offspring of Sprague-Dawley rats fed a low protein diet (casein, 80 g/kg) were randomly divided into two groups and weaned onto either the low protein diet or a control diet (casein, 180 g/kg). As a control group, offspring of rats fed the control diet were weaned onto the control diet. The rats in each group were randomly divided into four groups that were killed at 5, 10, 15 and 20 wk of age. Both mitochondrial DNA content and the expression of mitochondrial DNA-encoded genes in liver and muscle were measured. Mitochondrial transcription factor A and antioxidant enzyme activities were also determined. The mitochondrial DNA content of the liver and skeletal muscle were reduced in fetal and early postnatal malnourished rats even when proper nutrition was supplied after weaning. These changes were accompanied by a decrease in mitochondrial DNA-encoded gene expression; however, they were not dependent on mitochondrial transcriptional factor A. Our findings indicate that poor nutrition in early life causes long-lasting changes in mitochondria that may contribute to the development of insulin resistance in later life. J. Nutr. 133: 3085-3090, 2003. KEY WORDS: * fetal protein malnutrition * insulin resistance * mitochondrial DNA * mitochondrial transcription factors