Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training

PERSISTENT LOW-GRADE INFLAMMATION, as indicated by higher circulating levels of inflammatory mediators such as C-reactive protein, interleukin-6 and tumour necrosis factor-α, is a strong risk factor for several chronic diseases. There are data indicating that decreasing energy intake and increasing physical activity may be effective therapies for reducing overall inflammation. Evidence is strong that circulating levels of inflammatory markers are elevated with total and abdominal obesity, possibly owing to a higher secretion rate of cytokines by adipose tissue in obese people. Moreover, very-low-energy dietary weight loss reduces both circulating markers of inflammation and adipose-tissue cytokine production. Data from several large population-based cohorts show an inverse association between markers of systemic inflammation and physical activity or fitness status; small-scale intervention studies support that exercise training diminishes inflammation. Dietary weight loss plus exercise is likely more effective than weight reduction alone in reducing inflammation. To date, data from randomized, controlled trails designed to definitively test the effects of weight loss or exercise training, or both, on inflammation are limited. Future studies are required to define the amount of weight loss needed for clinically meaningful reductions of inflammation; in addition, fully powered and controlled studies are necessary to clarify the effect of exercise training on chronic, systemic inflammation.The biologic cascade of events that form the body''s natural defenses against injury or infection is a vital part of the immune system. Ordinarily, this process is an acute response resulting in rapid, major increases in inflammatory mediators released into the circulation.^1,2 In healthy, lean, non-elderly people, for example, blood concentrations of the acute-phase reactant C-reactive protein (CRP), which are normally less than 2 mg/L in men³ and less than 2.5 mg/ L in women,⁴ can increase more than 1000-fold in response to infection or trauma.^2,5,6Typically, a CRP value of 10 mg/L or more is considered indicative of clinically significant inflammation.⁷ However, recent evidence indicates that persistent elevations in circulating markers of inflammation, even when within the clinically normal range, are risk factors for cardiovascular disease in both middle-aged^{8,9,10,11,12,13} and older^{14,15,16,17,18,19} people. Recently, the US Centers for Disease Control and Prevention and the American Heart Association have stated that people with CRP values in the upper tertile of the adult population (> 3.0 mg/L) have a risk of cardiovascular disease that is double that of people whose CRP concentrations are less than 1.0 mg/L.²⁰ In addition to CRP, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), along with several other acute-phase reactant proteins, cytokines and cytokine-soluble receptors, are strongly associated with increased risk for several chronic diseases, including cardiovascular disease,^12,17,21,22 diabetes mellitus^23,24 and disability.^25,26 IL-6 and TNF-α are both stimulators of CRP release from hepatocytes.^27,28 It is not yet known which of these factors might be the most robust indicator of underlying inflammation, or whether the effects of these biomarkers are additive for risk prediction.As illustrated in Figure 1, behavioural factors are associated with chronic, low-grade states of inflammation (as measured by slightly elevated inflammatory biomarkers), and therefore with the several chronic diseases that are associated with inflammatory states. Since the risk estimates associated with elevated inflammation appear to be linear (e.g., the CRP category cut-offs for assessment of cardiovascular disease risk²⁰ are low risk < 1.0 mg/L, medium risk 1.0–3.0 mg/L and high risk > 3.0 mg/L), behavioural interventions that produce even slight reductions in inflammation may have clinically significant benefits. A few pharmacologic interventions such as use of angiotensin-converting-enzyme inhibitors and statins decrease inflammation, as evidenced by lowered CRP concentrations in prospective clinical trials.^29,30,31,32 Moreover, there are very promising data suggesting that decreasing body weight and increasing physical activity are just as effective as medication for reducing overall inflammation. The published effects of behavioural interventions involving weight loss and exercise training on inflammatory markers are reviewed here.Open in a separate windowFig. 1: Reported behavioural factors associated with chronic subclinical inflammation, and diseases and adverse health conditions for which inflammation is a risk factor. ↓ = decreased; BMI = body mass index.     

Gender Differences in the Response of Plasma Leptin Concentrations to Weight Loss in Obese Older Individuals

Plasma leptin concentration is directly related to the degree of obesity and is higher in women than in men of the same body mass index (BMI). We hypothesized that fasting plasma leptin concentrations and the response of leptin to weight loss would differ in older men and women of a similar fat mass. Plasma leptin concentrations (radioimmunoassay) and fat mass (DXA) were measured in 47 older, obese (BMI=30 ± 4 kg/m²) women and 23 older, obese (BMI=31 ± 3 kg/m²) men after a 2 to 4 week period of weight and dietary stabilization, and then in 22 of the women and 18 of the men after a 6-month weight loss intervention (250–350 kcal/d deficit). Leptin correlated with fat mass in men and women (r=0.75 and r=0.77, respectively; p values<0.0001), but women had 3-fold higher leptin levels for a given fat mass than men (p=0.01). In response to the 6-month hypocaloric diet, men and women lost a similar percentage of fat mass (?13% and ?16%, respectively), but the relative decline in circulating leptin was greater in women than men (-45% and ?21%, respectively; p<0.0001). In addition, when leptin was normalized for fat mass using the ratio method, the decrease in leptin per kilogram of fat mass was greater in women than men (-0.37 ± 0.34 vs. ?0.04 ± 0.06 ng/mL/kg; p<0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r=0.60; p<0.01), but not in women (r=0.31; p=0.17). Furthermore, the loss in fat mass correlated negatively with baseline leptin levels in women (r=-0.47; p<0.05), but not in men (r=0.03, p=NS). These results indicate that the decline in leptin concentration with weight loss correlates with the loss in fat mass in men; but, in women, other factors affect the decrease in leptin concentration. This suggests that the role of leptin in the regulation of obesity is gender-specific and may account for gender differences in response to hypocaloric treatment and maintenance of lost weight.     

Compartmentation of citric acid cycle metabolism in brain: effect of aminooxyacetic acid, ouabain and Ca2+ on the labelling of glutamate, glutamine, aspartate and gaba by [1-14C]acetate, [U-14C]glutamate and [U-14C]asparate

—(1) The effects of aminooxyacetic acid, ouabain and Ca²⁺ on the compartmentation of amino acid metabolism have been studied in slices of brain incubated with sodium-[1-¹⁴C]acetate, l-[U-¹⁴C]glutamate and l-[U-¹⁴C]aspartate as tracer metabolites. (2) Aminooxyacetic acid (10^-3 m) inhibited the labelling of aspartate from [¹⁴C]acetate and [¹⁴C]glutamate, as well as the incorporation of label from [¹⁴C]aspartate into glutamate and glutamine. It also inhibited the labelling of GABA from all three radioactive precursors, as would be anticipated if there was inhibition of several transaminases as well as glutamate decarboxylase. The RSA of glutamine labelled from [1-¹⁴C]acetate was increased. This finding indicated that the glutamate pool which is utilized for glutamine formation is associated with glutamate dehydrogenase, and this enzyme appears to be related to the ‘synthetic tricarboxylic acid cycle’. AOAA exerted its major inhibitory effects on the citric acid‘energy cycle’with which transaminases are associated. (3) Ouabain (10^-5 m) inhibited the labelling of glutamine to a much greater extent than the labelling of glutamate from [1-¹⁴C]acetate. It also caused leakage of amino acids from the tissue into the medium. Its effect on the glutamate–glutamine system was interpreted to be a selective inhibition of the 'synthetic’citric acid cycle. (4) The omission of Ca²⁺ from the incubation medium was associated with formation of glutamine with RSA less than 1·0 when labelled from [U-¹⁴C]glutamate, [U-¹⁴C]aspartate and lower than normal when labelled from [1-¹⁴C]acetate.     

A Bead-Based Multiplex Assay for the Detection of DNA Viruses Infecting Laboratory Rodents

The Federation of European Laboratory Animal Science Association (FELASA) recommends screening of laboratory rodents and biological materials for a broad variety of bacterial agents, viruses, and parasites. Methods commonly used to date for pathogen detection are neither cost-effective nor time- and animal-efficient or uniform. However, an infection even if silent alters experimental results through changing the animals’ physiology and increases inter-individual variability. As a consequence higher numbers of animals and experiments are needed for valid and significant results. We developed a novel high-throughput multiplex assay, called rodent DNA virus finder (rDVF) for the simultaneous identification of 24 DNA viruses infecting mice and rats. We detected all 24 DNA viruses with high specificity and reproducibility. Detection limits for the different DNA viruses varied between 10 and 1000 copies per PCR. The validation of rDVF was done with DNA isolated from homogenised organs amplified by pathogen specific primers in one multiplex PCR. The biotinylated amplicons were detected via hybridisation to specific oligonucleotide probes coupled to spectrally distinct sets of fluorescent Luminex beads. In conclusion, rDVF may have the potential to replace conventional testing and may simplify and improve routine detection of DNA viruses infecting rodents.     

4'-alkylated analogs of 1-methyl-4-phenylpyridinium ion are potent inhibitors of mitochondrial respiration

1-Methyl-4-phenylpyridinium ion, a major brain metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is an inhibitor of Complex I of the mitochondrial respiratory chain. We have synthesized several analogs of 1-methyl-4-phenylpyridinium ion containing various alkyl groups in the 4' position of the phenyl ring and have tested them for their abilities to inhibit the oxidation of NADH-linked substrates by intact mouse liver mitochondria. These compounds are considerably more potent inhibitors than MPP+ itself, with potency increasing as the length of the alkyl chain increases. The most potent inhibitor, 1-methyl-4-(4'heptylphenyl)pyridinium ion, was about 200 times as effective as MPP+. These analogs should prove to be useful tools for studying the nature of the process whereby MPP+ and its pyridinium analogs interact with Complex I to inhibit mitochondrial respiration.     

The effect of redox state on the folding free energy of azurin

 The unfolding of oxidized and reduced azurin by guanidine hydrochloride has been monitored by circular dichroism. Dilution experiments showed the unfolding to be reversible, and the equilibrium data have been interpreted in terms of a two-state model. The protein is stabilized by the strong metal binding in the native state, so that the folding free energy is as high as –52.2 kJ mol^–1 for the oxidized protein. The reduced protein is less stable, with a folding free energy of –40.0 kJ mol^–1. A thermodynamic cycle shows, as a consequence, that unfolded azurin has a reduction potential 0.13 V above that of the folded protein. This is explained by the bipyramidal site in the native fold stabilizing Cu(II) by a rack mechanism, with the same geometry being maintained in the Cu(I) form. In the unfolded protein, on the other hand, the coordination geometries are expected to differ for the two oxidation states, Cu(I) being stabilized by the cysteine thiol group in a linear or trigonal symmetry, whereas Cu(II) prefers oxygen ligands in a tetragonal geometry. Received: 15 January 1997 / Accepted: 3 April 1997     

Detection of Pathogenic Viruses in Sewage Provided Early Warnings of Hepatitis A Virus and Norovirus Outbreaks

Most persons infected with enterically transmitted viruses shed large amounts of virus in feces for days or weeks, both before and after onset of symptoms. Therefore, viruses causing gastroenteritis may be detected in wastewater, even if only a few persons are infected. In this study, the presence of eight pathogenic viruses (norovirus, astrovirus, rotavirus, adenovirus, Aichi virus, parechovirus, hepatitis A virus [HAV], and hepatitis E virus) was investigated in sewage to explore whether their identification could be used as an early warning of outbreaks. Samples of the untreated sewage were collected in proportion to flow at Ryaverket, Gothenburg, Sweden. Daily samples collected during every second week between January and May 2013 were pooled and analyzed for detection of viruses by concentration through adsorption to milk proteins and PCR. The largest amount of noroviruses was detected in sewage 2 to 3 weeks before most patients were diagnosed with this infection in Gothenburg. The other viruses were detected at lower levels. HAV was detected between weeks 5 and 13, and partial sequencing of the structural VP1protein identified three different strains. Two strains were involved in an ongoing outbreak in Scandinavia and were also identified in samples from patients with acute hepatitis A in Gothenburg during spring of 2013. The third strain was unique and was not detected in any patient sample. The method used may thus be a tool to detect incipient outbreaks of these viruses and provide early warning before the causative pathogens have been recognized in health care.