Functional interleukin-6 receptor-α is located in tanycytes at the base of the third ventricle.

Interleukin (IL)-6- /- mice develop mature onset obesity, whereas i.c.v. injection of IL-6 decreases obesity in rodents. Moreover, levels of IL-6 in cerebrospinal fluid (CSF) were reported to be inversely correlated with obesity in humans. Tanycytes lining the base of the third ventricle (3V) in the hypothalamus have recently been reported to be of importance for metabolism. In the present study, we investigated whether tanycytes could respond to IL-6 in the CSF. With immunohistochemistry using a well characterised antibody directed against the ligand binding receptor for IL-6, IL-6 receptor α (IL-6Rα), it was found that tanycytes, identified by the two markers, vimentin and dopamine- and cAMP-regulated phosphoprotein of 32 kDa, contained IL-6Rα. There were fewer IL-6Rα on another type of ventricle-lining cells, ependymal cells, as identified by the marker glucose transporter-1. To demonstrate that the immunoreactive IL-6Rα were responsive to IL-6, we injected IL-6 i.c.v. This treatment increased immunoreactive phosphorylated signal transducer and activator of transcription-3 (pSTAT3) in tanycytes after 5 minutes and in cells in the medial part of the arcuate nucleus after 5 and 15 minutes. Intracerebroventricular injection of leptin exerted similar effects. As expected, i.p. injection of leptin also induced pSTAT3 staining in the hypothalamus, whereas i.p. IL-6 injection had little effect on this parameter. Intracerebroventricular or i.p. injection of vehicle only had no effect on pSTAT3-immunoreactivity. In summary, there are functional IL-6Rα on tanycytes at the bottom of the 3V, in agreement with the possibility that ventricular administration of IL-6 decreases obesity in mice via an effect on this cell type.

Metabolic and spatio-taxonomic response of uncultivated seafloor bacteria following the Deepwater Horizon oil spill.

The release of 700 million liters of oil into the Gulf of Mexico over a few months in 2010 produced dramatic changes in the microbial ecology of the water and sediment. Here, we reconstructed the genomes of 57 widespread uncultivated bacteria from post-spill deep-sea sediments, and recovered their gene expression pattern across the seafloor. These genomes comprised a common collection of bacteria that were enriched in heavily affected sediments around the wellhead. Although rare in distal sediments, some members were still detectable at sites up to 60 km away. Many of these genomes exhibited phylogenetic clustering indicative of common trait selection by the environment, and within half we identified 264 genes associated with hydrocarbon degradation. Alkane degradation ability was near ubiquitous among candidate hydrocarbon degraders, whereas just three harbored elaborate gene inventories for the degradation of alkanes and aromatic and polycyclic aromatic hydrocarbons (PAHs). Differential gene expression profiles revealed a spill-promoted microbial sulfur cycle alongside gene upregulation associated with PAH degradation. Gene expression associated with alkane degradation was widespread, although active alkane degrader identities changed along the pollution gradient. Analyses suggest that a broad metabolic capacity to respond to oil inputs exists across a large array of usually rare indigenous deep-sea bacteria.

Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass.

Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 µg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.

Fibroblast Biomarkers of Sporadic Parkinson's Disease and LRRK2 Kinase Inhibition.

It has been uncertain whether specific disease-relevant biomarker phenotypes can be found using sporadic Parkinson's disease (PD) patient-derived samples, as it has been proposed that there may be a plethora of underlying causes and pathological mechanisms. Fibroblasts derived from familial PD patients harboring leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Parkin mutations show clear disease-relevant mitochondrial phenotypes, which are exacerbated under conditions of pharmacological stress. We utilized fibroblasts derived from non-familial sporadic PD patients (without LRRK2 mutations) or LRRK2 mutation carriers to directly compare the cellular phenotypes during and after mitochondrial stress. We then determined the effects of pharmacological LRRK2 kinase inhibition using LRRK2-in-1. We found that there were two distinct populations of sporadic PD patient-derived fibroblast lines. One group of sporadic PD lines was highly susceptible to valinomycin-induced mitochondrial depolarization, emulating the mutant LRRK2 phenotype. These lines showed elevated mitochondrial superoxide/ nitric oxide levels, displayed increased mitochondrial and lysosome co-localization, and an increased rate of mitochondrial collapse, which corresponded with changes in mitochondrial fission and fusion proteins. The application of LRRK2-in-1 reversed decreased levels of mitochondrial and lysosome co-localization and partially restored mitochondrial network associated proteins and the mitochondrial membrane potential in the fibroblasts. This study identifies novel mitochondrial biomarkers in sporadic PD patient-derived fibroblast lines, which could be used as preclinical tools in which to test novel and known neuroprotective compounds.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Snus (Swedish smokeless tobacco) use and risk of stroke: pooled analyses of incidence and survival.

BACKGROUND: Snus is a moist smokeless tobacco product with high nicotine content. Its use has a short-term effect on the cardiovascular system, but the relationship between snus use and stroke is unclear. OBJECTIVE: The aim of this study was to assess the associations between use of snus and incidence of and survival after stroke, both overall and according to subtypes. METHODS: Pooled analyses of eight Swedish prospective cohort studies were conducted, including 130 485 men who never smoked. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of incidence and death after diagnosis using Cox proportional hazard regression models and case fatality and survival using logistic regression and Kaplan-Meier methods, respectively. RESULTS: No associations were observed between the use of snus and the risk of overall stroke (HR 1.04, 95% CI 0.92-1.17) or of any of the stroke subtypes. The odds ratio (OR) of 28-day case fatality was 1.42 (95% CI 0.99-2.04) amongst users of snus who had experienced a stroke, and the HR of death during the follow-up period was 1.32 (95% CI 1.08-1.61). CONCLUSION: Use of snus was not associated with the risk of stroke. Hence, nicotine is unlikely to contribute importantly to the pathophysiology of stroke. However, case fatality was increased in snus users, compared with nonusers, but further studies are needed to determine any possible causal mechanisms.

Inter-relation between interleukin (IL)-1, IL-6 and body fat regulating circuits of the hypothalamic arcuate nucleus.

Interleukin (IL)-1 and IL-6 are immune modulating cytokines that also affect metabolic function because both IL-1 receptor I deficient (IL-1RI⁻/⁻) and IL-6 deficient (IL-6⁻/⁻) mice develop late-onset obesity and leptin resistance. Both IL-1 and IL-6 appear to target the central nervous system (CNS) to increase energy expenditure. The hypothalamic arcuate nucleus (ARC) is a major relay between the periphery and CNS in body fat regulation (e.g. by being a target of leptin). The present study aimed to investigate the possible mechanisms responsible for the effects exerted by endogenous IL-1 and IL-6 on body fat at the level of the ARC, as well as possible interactions between IL-1 and IL-6. Therefore, we measured the gene expression of neuropeptides of the ARC involved in energy balance in IL-1RI⁻/⁻ and IL-6⁻/⁻ mice. We also investigated the interactions between expression of IL-1 and IL-6 in these mice, and mapped IL-6 receptor α (IL-6Rα) in the ARC. The expression of the obesity promoting peptide neuropeptide Y (NPY), found in the ARC, was increased in IL-1RI⁻/⁻ mice. The expression of NPY and agouti-related peptide (AgRP), known to be co-expressed with NPY in ARC neurones, was increased in cold exposed IL-6⁻/⁻ mice. IL-6Rα immunoreactivity was densely localised in the ARC, especially in the medial part, and was partly found in NPY positive cell bodies and also α-melanocyte-stimulating hormone positive cell bodies. The expression of hypothalamic IL-6 was decreased in IL-1RI⁻/⁻ mice, whereas IL-1ß expression was increased in IL-6⁻/⁻ mice. The results of the present study indicate that depletion of the activity of the fat suppressing cytokines IL-1 and IL-6 in knockout mice can increase the expression of the obesity promoting neuropeptide NPY in the ARC. Depletion of IL-1 activity suppresses IL-6 expression, and IL-6Rα-like immunoreactivity is present in neurones in the medial ARC, including neurones containing NPY. Therefore, IL-6, IL-1 and NPY/AgRP could interact at the level of the hypothalamic ARC in the regulation of body fat.

Dietary fibre intake and ischaemic heart disease mortality: the European Prospective Investigation into Cancer and Nutrition-Heart study.

BACKGROUND/OBJECTIVES: Evidence from prospective studies is consistent in showing an inverse association between dietary fibre intake and risk of ischaemic heart disease (IHD), but whether dietary fibre from various food sources differ in their effect on IHD risk is less clear. The objective of this study was to assess the associations of total and food sources of dietary fibre with IHD mortality in the European Prospective Investigation into Cancer and Nutrition-Heart study. SUBJECTS/METHODS: Participants were 306,331 men and women from eight European countries. Dietary fibre intake was assessed using centre or country-specific diet questionnaires and calibrated using a 24-h diet recall. RESULTS: After an average follow-up of 11.5 years, there were 2381 IHD deaths among participants without cardiovascular disease at baseline. The calibrated intake of dietary fibre was inversely related with IHD mortality; each 10 g/day was associated with a 15% lower risk (relative risk (RR) 0.85; 95% confidence interval (CI): 0.73-0.99, P=0.031). There was no difference in the associations of the individual food sources of dietary fibre with the risk of IHD mortality; RR for each 5 g/day higher cereal fibre intake was 0.91 (CI: 0.82-1.01), RR for each 2.5 g/day fruit fibre intake was 0.94 (CI: 0.88-1.01) and RR for each 2.5 g/day vegetable fibre intake was 0.90 (95% CI: 0.76-1.07). CONCLUSION: A higher consumption of dietary fibre is associated with a lower risk of fatal IHD with no clear difference in the association with IHD for fibre from cereals, fruits or vegetables.

Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to estimate the relative risk of cardiovascular disease (CVD) among people living with HIV (PLHIV) compared with the HIV-uninfected population. METHODS: We conducted a systematic review and meta-analysis of studies from the peer-reviewed literature. We searched the Medline database for relevant journal articles published before August 2010. Eligible studies were observational and randomized controlled trials, reporting CVD, defined as myocardial infarction (MI), ischaemic heart disease, cardiovascular and cerebrovascular events or coronary heart disease among HIV-positive adults. Pooled relative risks were calculated for various groupings, including different classes of antiretroviral therapy (ART). RESULTS: The relative risk of CVD was 1.61 [95% confidence interval (CI) 1.43-1.81] among PLHIV without ART compared with HIV-uninfected people. The relative risk of CVD was 2.00 (95% CI 1.70-2.37) among PLHIV on ART compared with HIV-uninfected people and 1.52 (95% CI 1.35-1.70) compared with treatment-naïve PLHIV. We estimate the relative risk of CVD associated with protease inhibitor (PI)-, nucleoside reverse transcriptase inhibitor- and nonnucleoside reverse transcriptase inhibitor-based ART to be 1.11 (95% CI 1.05-1.17), 1.05 (95% CI 1.01-1.10) and 1.04 (95% CI 0.99-1.09) per year of exposure, respectively. Not all ART was associated with increased risk; specifically, lopinavir/ritonavir and abacavir were associated with the greater risk and the relative risk of MI for PI-based versus non-PI-based ART was 1.41 (95% CI 1.20-1.65). CONCLUSION: PLHIV are at increased risk of cardiovascular disease. Although effective in prolonging survival, ART (in particular PI-based regimens) is related to further increased risk of CVD events among people at highest initial absolute risk of cardiovascular disease.

Low-carbohydrate, high-protein score and mortality in a northern Swedish population-based cohort.

BACKGROUND/OBJECTIVE: Long-term effects of carbohydrate-restricted diets are unclear. We examined a low-carbohydrate, high-protein (LCHP) score in relation to mortality. SUBJECTS/METHODS: This is a population-based cohort study on adults in the northern Swedish county of Västerbotten. In 37,639 men (1460 deaths) and 39,680 women (923 deaths) from the population-based Västerbotten Intervention Program, deciles of energy-adjusted carbohydrate (descending) and protein (ascending) intake were added to create an LCHP score (2-20 points). Sex-specific hazard ratios (HR) were calculated by Cox regression. RESULTS: Median intakes of carbohydrates, protein and fat in subjects with LCHP scores 2-20 ranged from 61.0% to 38.6%, 11.3% to 19.2% and 26.6% to 41.5% of total energy intake, respectively. High LCHP score (14-20 points) did not predict all-cause mortality compared with low LCHP score (2-8 points), after accounting for saturated fat intake and established risk factors (men: HR for high vs low 1.03 (95% confidence interval (CI) 0.88-1.20), P for continuous = 0.721; women: HR for high vs low 1.10 (95% CI 0.91-1.32), P for continuous = 0.229). For cancer and cardiovascular disease, no clear associations were found. Carbohydrate intake was inversely associated with all-cause mortality, though only statistically significant in women (multivariate HR per decile increase 0.95 (95% CI 0.91-0.99), P = 0.010). CONCLUSION: Our results do not support a clear, general association between LCHP score and mortality. Studies encompassing a wider range of macronutrient consumption may be necessary to detect such an association.

Interleukin-6 receptor α is co-localised with melanin-concentrating hormone in human and mouse hypothalamus.

Interleukin (IL)-6 deficient mice develop mature-onset obesity. Furthermore, i.c.v. administration of IL-6 increases energy expenditure, suggesting that IL-6 centrally regulates energy homeostasis. To investigate whether it would be possible for IL-6 to directly influence the energy homeostasis via hypothalamic regulation in humans and rodents, we mapped the distribution of the ligand binding IL-6 receptor α (IL-6Rα) in this brain region. In the human hypothalamus, IL-6Rα-immunoreactivity was detected in perikarya and first-order dendrites of neurones. The IL-6Rα-immunoreactive (-IR) neurones were observed posterior to the level of the interventricular foramen. There, IL-6Rα-IR neurones were located in the lateral hypothalamic, perifornical, dorsal and posterior hypothalamic areas, the hypothalamic dorsomedial nucleus and in the zona incerta. In the caudal part of the hypothalamus, the density of the IL-6Rα-IR neurones gradually increased. Double-labelling immunofluorescent studies demonstrated that IL-6Rα immunoreactivity was localised in the same neurones as the orexigenic neuropeptide, melanin-concentrating hormone (MCH). By contrast, IL-6Rα-immunoreactivity was not observed in the orexin B-IR neurones. To determine whether the observed expression of IL-6Rα is evolutionary conserved, we studied the co-localisation of IL-6Rα with MCH and orexin in the mouse hypothalamus, where IL-6Rα-immunoreactivity was present in numerous MCH-IR and orexin-IR neurones. Our data demonstrate that the MCH neurones of the human hypothalamus, as well as the MCH and orexin neurones of the mouse hypothalamus, contain IL-6Rα. This opens up the possibility that IL-6 influences the energy balance through the MCH neurones in humans, and both MCH and orexin neurones in mice.

Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment.

AIMS: Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this longitudinal cohort study of OAC-treated patients, we aimed to evaluate the relationship between von Willebrand factor (VWF) levels and risk of bleeding complications, cardiovascular mortality and all-cause mortality. METHODS AND RESULTS: A total of 719 patients receiving warfarin treatment were observed for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified into clinically relevant bleeding (CRB) and major bleeding. Ischaemic stroke, peripheral arterial embolism, myocardial infarction, and death were also recorded. We identified 113 cases of CRB and 73 of major bleeding. In total, 161 deaths occurred during follow-up with cardiovascular disease identified as the cause of death in 110 patients. Patients in the highest tertile of VWF had a significantly increased risk of bleeding complications: hazard ratio (HR) 2.53 (95% CI 1.41-4.56) for major bleeding and HR 2.19 (95% CI 1.38-3.48) for CRB. VWF, expressed either in tertiles or as a continuous variable, showed a significant association with cardiovascular mortality (HR 1.68, 95% CI 1.40-2.01) and all-cause mortality (HR 1.77, 95% CI 1.52-2.05). In multivariate Cox regression analysis, the findings remained significant after adjusting for age, high-sensitivity C-reactive protein and creatinine. CONCLUSIONS: Patients with high levels of VWF had an increased risk of bleeding complications, cardiovascular mortality and all-cause mortality during OAC treatment. Our findings imply that the use of VWF as a risk marker for thromboembolic events is complicated by the association of VWF with bleeding complications.

Low bone mineral density is associated with increased risk for myocardial infarction in men and women.

UNLABELLED: The association between bone mineral density (BMD) and myocardial infarction (MI) was investigated in 6,872 men and women. For both men and women, lower BMD in the femoral neck and hip was associated with increased risk of MI largely independent of smoking, hypertension, hypertriglyceridemia, and diabetes. INTRODUCTION: The relationship between BMD and cardiovascular disease is not completely understood. The objective of this prospective study was to investigate the risk of MI in relation to bone mineral density and to determine if cardiovascular risk factors could explain this association. METHODS: Dual energy X-ray absorptiometry was performed in 5,490 women and 1,382 men to determine total hip and femoral neck BMD (in grams per square centimeters) and estimate femoral neck volumetric BMD (in grams per cubic centimeters). During a mean follow-up time of 5.7 years, 117 women and 79 men suffered an initial MI. RESULTS: After adjustment for age and BMI, lower BMD of the femoral neck and total hip was associated with increased risk of MI for both women [hazard ratio (HR) = 1.33, 95% confidence interval (CI) 1.08-1.66 per standard deviation (SD) decrease in femoral neck BMD] and men (HR = 1.74, 95% CI 1.34-2.28 per SD decrease in total hip BMD). After additional adjustment for smoking, hypertension, hypertriglyceridemia, and diabetes, the associations were slightly attenuated in men (HR = 1.42-1.88 in the age and BMI-adjusted model versus 1.33-1.77 in the fully adjusted model) while similar attenuations were seen in women (HR = 1.06-1.25 versus 1.05-1.22). CONCLUSION: Lower BMD was associated with an increase in MI risk for both men and women. Women had consistently lower HRs compared to men in all models. Adjusting for smoking, hypertension, hypertriglyceridemia, and diabetes did not distinctively weaken these associations.

The disparity between long-term survival in patients with and without diabetes following a first myocardial infarction did not change between 1989 and 2006: an analysis of 6,776 patients in the Northern Sweden MONICA Study.

AIMS/HYPOTHESIS: Long-term survival after myocardial infarction (MI) has improved in the population, but data on diabetic patients is lacking. We analysed survival for up to 18 years after a first MI in patients with or without diabetes. METHODS: The Northern Sweden MONICA Myocardial Infarction Registry was linked to the Cause-of-Death Registry for a total of 6,776 patients, 25-64 years of age, with a first MI during 1989-2006. Prehospital deaths were included. Follow-up ended on 30 August 2008. RESULTS: Sixteen per cent had diabetes. Median follow-up time was 6.8 years, and the study included 50,667 patient-years. One third of the non-diabetic patients died vs half of the diabetic patients. Median survival for non-diabetic men was 227 months and for diabetic men 123 months. Corresponding figures for the non-diabetic and diabetic women were 222 and 81 months respectively. Men with diabetes had an age-adjusted HR for all-cause mortality of 1.56 (95% CI 1.39, 1.79) vs men without diabetes. Mortality risk was higher among diabetic women, HR 1.97 (1.62, 2.39) (diabetes × sex interaction, p = 0.03). Survival increased for three consecutive cohorts and was higher in non-diabetic patients for all durations of follow-up and in all three cohorts. The interaction of diabetes x cohort was not significant over time (p = 0.5) and HRs did not differ either. CONCLUSIONS/INTERPRETATION: Long-term survival after a first MI is markedly lower in diabetic patients, especially among women, over an 18-year observation time. Although survival has improved in diabetic patients, the effect of diabetes upon mortality has not diminished.

Large improvements in major cardiovascular risk factors in the population of northern Sweden: the MONICA study 1986-2009.

OBJECTIVES: the incidence of cardiovascular disease has declined rapidly in Sweden since the 1980s. We explored changes in major cardiovascular risk factors in northern Sweden between 1986 and 2009. DESIGN: since 1986, six population surveys have been carried out in northern Sweden using procedures of the World Health Organization MONICA project. The population age range was 25-64 years in 1986 and 1990, and 25-74 years from 1994. Trends were analysed using generalized linear models. RESULTS: a total of 10586 subjects were included in the surveys. Blood pressure decreased by 4.9/3.9 mmHg in women and 1.8/1.5 mmHg in men aged 25-64 years between 1986 and 2009. In men and women aged 65-74 years, the decrease was 12.6/6.1 mmHg between 1994 and 2009. From 1994, the use of blood pressure-lowering drugs increased, particularly among the older subgroup. The prevalence of smoking halved between 1986 and 2009; 11% of women and 9% of men were smokers in 2009. Cholesterol levels decreased by 0.9 mmol L(-1) in the younger age group (25-64 years), and the use of lipid-lowering agents increased from 1994. Among subjects aged 25-64 years, one in five was obese in 2009, which was twice as many as in 1986, and body mass index (BMI) increased by 1.5 kg m(-2) , corresponding to an increase in weight of 4 kg. There was no further increase in BMI from 2004. The prevalence of diabetes did not change between 1986 and 2009. The proportion that received a university education increased markedly in all age groups, especially in women, during the study period. CONCLUSIONS: significant improvements were observed in major cardiovascular risk factors in northern Sweden between 1986 and 2009.

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance.

AIMS/HYPOTHESIS: The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 (-/-)) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. METHODS: Male, 8-week-old Il6 (-/-) and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. RESULTS: Il6 (-/-) mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 (-/-) and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 (-/-) mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 (-/-) relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme ß-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. CONCLUSIONS/INTERPRETATION: Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

Abdominal and gynoid adipose distribution and incident myocardial infarction in women and men.

OBJECTIVE: The relationships between objectively measured abdominal and gynoid adipose mass with the prospective risk of myocardial infarction (MI) has been scarcely investigated. We aimed to investigate the associations between fat distribution and the risk of MI. SUBJECTS: Total and regional fat mass was measured using dual-energy X-ray absorptiometry (DEXA) in 2336 women and 922 men, of whom 104 subsequently experienced an MI during a mean follow-up time of 7.8 years. RESULTS: In women, the strongest independent predictor of MI was the ratio of abdominal to gynoid adipose mass (hazard ratio (HR)=2.44, 95% confidence interval (CI) 1.79-3.32 per s.d. increase in adipose mass), after adjustment for age and smoking. This ratio also showed a strong association with hypertension, impaired glucose tolerance and hypertriglyceridemia (P<0.01 for all). In contrast, the ratio of gynoid to total adipose mass was associated with a reduced risk of MI (HR= 0.57, 95% CI 0.43-0.77), and reduced risk of hypertension, impaired glucose tolerance and hypertriglyceridemia (P<0.001 for all). In men, gynoid fat mass was associated with a decreased risk of MI (HR=0.69, 95% CI 0.48-0.98), and abdominal fat mass was associated with hypertriglyceridemia (P for trend 0.02). CONCLUSION: In summary, fat distribution was a strong predictor of the risk of MI in women, but not in men. These different results may be explained by the associations found between fat distribution and hypertension, impaired glucose tolerance and hypertriglyceridemia.