Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.

Permanent changes in growth and physiology of Bacillus subtilis ToC46 after loss of a recombinant plasmid

The physiology and growth of plasmid-bearing Bacillus subtilis carrying plasmid pPFF1, the non-transformed host, and cells after loss of the plasmid (so-called plasmid-cured cells) were investigated. It was found that, following plasmid loss, cells exhibited phenotypic characteristics different from those of the non-transformed host strains. Compared to plasmid-bearing cells and non-transformed host cells, an approximate 25% increase in the maximum specific growth rate and a more rapid increase in total RNA per unit cell mass were observed in plasmid-cured cells. The total enthalpy associated with irreversible denaturation events was determined in whole cells by differential scanning calorimetry. This showed higher enthalpies for plasmid-cured cells compared with the non-transformed host, which suggests increased ribosome numbers. The result from cellular DNA hybridisation suggests that there was no direct evidence of plasmid integration into the host chromosome. (C) 2004 Elsevier Inc. All rights reserved.

Changes in fat, fat-free mass and body water in human normal pregnancy

Measurements of body weight, total body water and total body potassium (40K) were made serially on three occasions during pregnancy and once post partum in 27 normal pregnant women. Skinfold thickness and fat cell diameter were also measured. A model of body composition was formulated to permit the estimation of changes in fat, lean tissue and water content of the maternal body. Total maternal body fat increased during pregnancy, reaching a peak towards the end of the second trimester before diminishing. Serial measurements of fat cell diameter showed poor correlation, whilst total body fat calculated from skinfold thickness correlated well with our estimated values for total body fat in pregnancy.

Body mass, territory size and life history tactics in a socially monogamous canid, the red fox Vulpes vulpes

Male-biased sexual size dimorphism is typical of polygynous mammals, where the degree of dimorphism in body mass is related to male intrasexual competition and the degree of polygyny. However, the importance of body mass in monogamous mammals is largely unknown. We investigated the effect of body mass on life-history parameters and territory size in the red fox (Vulpes vulpes), a socially monogamous canid with slight sexual dimorphism. Increased body size in males appeared to confer an advantage in territory acquisition and defense contests because heavier males held larger territories and exerted a greater boundary pressure on smaller neighbors. Heavier male foxes invested more effort in searching for extrapair matings by moving over a wider area and farther from their territories, leading to greater reproductive success. Males that sired cubs outside their own social group appeared to be heavier than males that only sired cubs within their social group or that were cuckolded, but our results should be treated with caution because sample sizes were small. Territory size, boundary pressure, and paternity success were not related to age of males. In comparison, body mass of females was not related to territory size, probability of breeding, litter size, or cub mass. Only age affected probability of breeding in females: younger females reproduced significantly less than did older females, although we did not measure individual nutritional status. Thus, body mass had a significant effect on life-history traits and territory size in a socially monogamous species comparable to that reported in polygynous males, even in the absence of large size dimorphism.

Environmental variation at the onset of independent foraging affects full-grown body mass in the red fox

The period following the withdrawal of parental care has been highlighted as a key developmental period for juveniles. One reason for this is that juveniles cannot forage as competently as adults, potentially placing them at greater risk from environmentally-induced changes in food availability. However, no study has examined this topic. Using a long-term dataset on red foxes (Vulpes vulpes), we examined (i) dietary changes that occurred in the one-month period following the attainment of nutritional independence, (ii) diet composition in relation to climatic variation, and (iii) the effect of climatic variation on subsequent full-grown mass. Diet at nutritional independence contained increased quantities of easy-to-catch food items (earthworms and insects) when compared with pre-independence. Interannual variation in the volume of rainfall at nutritional independence was positively correlated to the proportion of earthworms in cub diet. Pre-independence cub mass and rainfall immediately following nutritional independence explained a significant proportion of variance in full-grown mass, with environmental variation affecting full-grown mass of the entire cohorts. Thus, weather-mediated availability of easy-to-catch food items at a key developmental stage has lifelong implications for the development of juvenile foxes by affecting full-grown mass, which in turn appears to be an important component of individual reproductive potential.

Combined affinity labelling and mass spectrometry analysis of differential cell surface protein expression in normal and prostate cancer cells

Differences in the expression of cell surface proteins between a normal prostate epithelial (1542-NP2TX) and a prostate cancer cell line (1542-CP3TX) derived from the same patient were investigated. A combination of affinity chromatographic purification of biotin-tagged surface proteins with mass spectrometry analysis identified 26 integral membrane proteins and 14 peripheral surface proteins. The findings confirm earlier reports of altered expression in prostate cancer for several cell surface proteins, including ALCAM/CD166, the Ephrin type A receptor, EGFR and the prostaglandin F2 receptor regulatory protein. In addition, several novel findings of differential expression were made, including the voltage-dependent anion selective channel proteins Porin 1 and 2, ecto-5'-nucleotidase (CD73) and Scavenger receptor B1. Cell surface protein expression changed both qualitatively and quantitatively when the cells were grown in the presence of either or both interferon INFalpha and INFgamma. Costimulation with type I and II interferons had additive or synergistic effects on the membrane density of several, mainly peripherally attached surface proteins. Concerted upregulation of surface exposed antigens may be of benefit in immuno-adjuvant-based treatment of interferon-responsive prostate cancer. In conclusion, this study demonstrates that differences in the expression of membrane proteins between normal and prostate cancer cells are reproducibly detectable following vectorial labelling with biotin, and that detailed analysis of extracellular-induced surface changes can be achieved by combining surface-specific labelling with high-resolution two-dimensional gel electrophoresis and mass spectrometry.

Bergmann's rule and body size in mammals

Aim: To describe the geographical pattern of mean body size of the non-volant mammals of the Nearctic and Neotropics and evaluate the influence of five environmental variables that are likely to affect body size gradients. Location: The Western Hemisphere. Methods: We calculated mean body size (average log mass) values in 110 × 110 km cells covering the continental Nearctic and Neotropics. We also generated cell averages for mean annual temperature, range in elevation, their interaction, actual evapotranspiration, and the global vegetation index and its coefficient of variation. Associations between mean body size and environmental variables were tested with simple correlations and ordinary least squares multiple regression, complemented with spatial autocorrelation analyses and split-line regression. We evaluated the relative support for each multiple-regression model using AIC. Results: Mean body size increases to the north in the Nearctic and is negatively correlated with temperature. In contrast, across the Neotropics mammals are largest in the tropical and subtropical lowlands and smaller in the Andes, generating a positive correlation with temperature. Finally, body size and temperature are nonlinearly related in both regions, and split-line linear regression found temperature thresholds marking clear shifts in these relationships (Nearctic 10.9 °C; Neotropics 12.6 °C). The increase in body sizes with decreasing temperature is strongest in the northern Nearctic, whereas a decrease in body size in mountains dominates the body size gradients in the warmer parts of both regions. Main conclusions: We confirm previous work finding strong broad-scale Bergmann trends in cold macroclimates but not in warmer areas. For the latter regions (i.e. the southern Nearctic and the Neotropics), our analyses also suggest that both local and broad-scale patterns of mammal body size variation are influenced in part by the strong mesoscale climatic gradients existing in mountainous areas. A likely explanation is that reduced habitat sizes in mountains limit the presence of larger-sized mammals.

Combined affinity labelling and mass spectrometry analysis of differential cell surface protein expression in normal and prostate cancer cells

Differences in the expression of cell surface proteins between a normal prostate epithelial (1542-NP2TX) and a prostate cancer cell line (1542-CP3TX) derived from the same patient were investigated. A combination of affinity chromatographic purification of biotin-tagged surface proteins with mass spectrometry analysis identified 26 integral membrane proteins and 14 peripheral surface proteins. The findings confirm earlier reports of altered expression in prostate cancer for several cell surface proteins, including ALCAM/CD166, the Ephrin type A receptor, EGFR and the prostaglandin F2 receptor regulatory protein. In addition, several novel findings of differential expression were made, including the voltage-dependent anion selective channel proteins Porin 1 and 2, ecto-5'-nucleotidase (CD73) and Scavenger receptor B1. Cell surface protein expression changed both qualitatively and quantitatively when the cells were grown in the presence of either or both interferon INF alpha and INF gamma. Costimulation with type I and II interferons had additive or synergistic effects on the membrane density of several, mainly peripherally attached surface proteins. Concerted upregulation of surface exposed antigens may be of benefit in immuno-adjuvant-based treatment of interferon-responsive prostate cancer. In conclusion, this study demonstrates that differences in the expression of membrane proteins between normal and prostate cancer cells are reproducibly detectable following vectorial labelling with biotin, and that detailed analysis of extracellular-induced surface changes can be achieved by combining surface-specific labelling with high-resolution two-dimensional gel electrophoresis and mass spectrometry.

Variation in the FFAR1 gene modifies BMI, body composition and plasma lipids but not plasma insulin or Beta-cell function in overweight subjects

Background FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids. Methodology/Principal Findings For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m2 higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI-increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six. Conclusions/Significance Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function.

Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene 1-3.

BACKGROUND: Intronic variation in the FTO (fat mass and obesity-associated) gene has been unequivocally associated with increased body mass index (BMI; in kg/m(2)) and the risk of obesity in populations of different ethnicity. OBJECTIVE: We examined whether this robust genetic predisposition to obesity can be attenuated by being more physically active. DESIGN: The FTO variant rs1121980 was genotyped in 20,374 participants (39-79 y of age) from the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, an ethnically homogeneous population-based cohort. Physical activity (PA) was assessed with a validated self-reported questionnaire. The interaction between rs1121980 and PA on BMI and waist circumference (WC) was examined by including the interaction term in mixed-effect models. RESULTS: We confirmed that the risk (T) allele of rs1121980 was significantly associated with BMI (0.31-unit increase per allele; P < 0.001) and WC (0.77-cm increase per allele; P < 0.001). The PA level attenuated the effect of rs1121980 on BMI and WC; ie, whereas in active individuals the risk allele increased BMI by 0.25 per allele, the increase in BMI was significantly (P for interaction = 0.004) more pronounced (76%) in inactive individuals (0.44 per risk allele). We observed similar effects for WC (P for interaction = 0.02): the risk allele increased WC by 1.04 cm per allele in inactive individuals but by only 0.64 cm in active individuals. CONCLUSIONS: Our results showed that PA attenuates the effect of the FTO rs1121980 genotype on BMI and WC. This observation has important public health implications because we showed that a genetic susceptibility to obesity induced by FTO variation can be overcome, at least in part, by adopting a physically active lifestyle.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

How body mass and lifestyle affect juvenile biomass production in placental mammals

In mammals, the mass-specific rate of biomass production during gestation and lactation, here called maternal productivity, has been shown to vary with body size and lifestyle. Metabolic theory predicts that post-weaning growth of offspring, here termed juvenile productivity, should be higher than maternal productivity, and juveniles of smaller species should be more productive than those of larger species. Furthermore because juveniles generally have similar lifestyles to their mothers, across species juvenile and maternal productivities should be correlated. We evaluated these predictions with data from 270 species of placental mammals in 14 taxonomic/lifestyle groups. All three predictions were supported. Lagomorphs, perissodactyls and artiodactyls were very productive both as juveniles and as mothers as expected from the abundance and reliability of their foods. Primates and bats were unproductive as juveniles and as mothers, as expected as an indirect consequence of their low predation risk and consequent low mortality. Our results point the way to a mechanistic explanation for the suite of correlated life-history traits that has been called the slow–fast continuum.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Background Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world's men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.

Accumulated metal speciation in earthworm populations with multi-generational exposure to metalliferous soils: cell fractionation and high energy synchrotron analyses

Predicting metal bioaccumulation and toxicity in soil organisms is complicated by site-specific biotic and abiotic parameters. In this study we exploited tissue fractionation and digestion techniques, combined with X-ray absorption spectroscopy (XAS), to investigate the whole-body and subcellular distributions, ligand affinities, and coordination chemistry of accumulated Pb and Zn in field populations of the epigeic earthworm Lumbricus rubellus inhabiting three contrasting metalliferous and two unpolluted soils. Our main findings were (i) earthworms were resident in soils with concentrations of Pb and Zn ranging from 1200 to 27 000 mg kg(-1) and 200 to 34 000 mg kg(-1), respectively; (ii) Pb and Zn primarily accumulated in the posterior alimentary canal in nonsoluble subcellular fractions of earthworms; (iii) site-specific differences in the tissue and subcellular partitioning profiles of populations were observed, with earthworms from a calcareous site partitioning proportionally more Pb to their anterior body segments and Zn to the chloragosome-rich subcellular fraction than their acidic-soil inhabiting counterparts; (iv) XAS indicated that the interpopulation differences in metal partitioning between organs were not accompanied by qualitative differences in ligand-binding speciation, because crystalline phosphate-containing pyromorphite was a predominant chemical species in the whole-worm tissues of all mine soil residents. Differences in metal (Pb, Zn) partitioning at both organ and cellular levels displayed by field populations with protracted histories of metal exposures may reflect their innate ecophysiological responses to essential edaphic variables, such as Ca2+ status. These observations are highly significant in the challenging exercise of interpreting holistic biomarker data delivered by "omic" technologies.

Predictions of the arrival time of coronal mass ejections at 1AU: an analysis of the causes of errors

Three existing models of Interplanetary Coronal Mass Ejection (ICME) transit between the Sun and the Earth are compared to coronagraph and in situ observations: all three models are found to perform with a similar level of accuracy (i.e. an average error between observed and predicted 1AU transit times of approximately 11 h). To improve long-term space weather prediction, factors influencing CME transit are investigated. Both the removal of the plane of sky projection (as suffered by coronagraph derived speeds of Earth directed CMEs) and the use of observed values of solar wind speed, fail to significantly improve transit time prediction. However, a correlation is found to exist between the late/early arrival of an ICME and the width of the preceding sheath region, suggesting that the error is a geometrical effect that can only be removed by a more accurate determination of a CME trajectory and expansion. The correlation between magnetic field intensity and speed of ejecta at 1AU is also investigated. It is found to be weak in the body of the ICME, but strong in the sheath, if the upstream solar wind conditions are taken into account.