Enhanced Fatty Acid Oxidation and FATP4 Protein Expression after Endurance Exercise Training in Human Skeletal Muscle

FATP1 and FATP4 appear to be important for the cellular uptake and handling of long chain fatty acids (LCFA). These findings were obtained from loss- or gain of function models. However, reports on FATP1 and FATP4 in human skeletal muscle are limited. Aerobic training enhances lipid oxidation; however, it is not known whether this involves up-regulation of FATP1 and FATP4 protein. Therefore, the aim of this project was to investigate FATP1 and FATP4 protein expression in the vastus lateralis muscle from healthy human individuals and to what extent FATP1 and FATP4 protein expression were affected by an increased fuel demand induced by exercise training. Eight young healthy males were recruited to the study. All subjects were non smokers and did not participate in regular physical activity (<1 time per week for the past 6 months, VO2peak 3.4±0.1 l O2 min−1). Subjects underwent an 8 week supervised aerobic training program. Training induced an increase in VO2peak from 3.4±0.1 to 3.9±0.1 l min−1 and citrate synthase activity was increased from 53.7±2.5 to 80.8±3.7 µmol g−1 min−1. The protein content of FATP4 was increased by 33%, whereas FATP1 protein content was reduced by 20%. Interestingly, at the end of the training intervention a significant association (r2 = 0.74) between the observed increase in skeletal muscle FATP4 protein expression and lipid oxidation during a 120 min endurance exercise test was observed. In conclusion, based on the present findings it is suggested that FATP1 and FATP4 proteins perform different functional roles in handling LCFA in skeletal muscle with FATP4 apparently more important as a lipid transport protein directing lipids for lipid oxidation

Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis

Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics. Sustarsic et al. reveal that synthesis of the mitochondrial phospholipid cardiolipin is a hallmark of brown and beige fat activation by cold temperature. This single lipid species in thermogenic fat not only shapes adipose mitochondrial bioenergetics but also exerts profound control over whole-body insulin sensitivity and metabolic flexibility.</p

Turnover time and production of planktonic crustacea in limed and reference portion of a bog lake

Bog lakes may be compared to engines which have operated on low-quality fuel and have, as a consequence, lost efficiency in the conversion of energy. Treatment of such lakes with hydrated lime provides at least a measure of temporary cor rection as inferred by the appearance of algal blooms (Waters 1957) and larger standing crops of zooplankton (Johnson and Hasler 1954, Waters and Ball 1957). The mechanisms by which alkalization augments production have been reviewed elsewhere (Stross and Hasler 1960). The observed increases in standing crops of primary consumers following treatment is presumed to reflect an increase in production at this trophic level. If the assumption is correct, there is, as yet, no good evidence that the increase is transferred to the plankton consumer. Johnson and Hasler found no increase in production of rainbow trout, a secondary consumer in early life, in a lake treated with lime despite the observed increase in the standing crop of Daphnia, the chief source of food for the trout in the lake. They attributed a part of the failure to reduced utilization resulting from dilution of food following a lime-induced increase in depth of the aerobic zone of the lake. The susceptibility of trout to stress when competing with other members of the same species (Brown 1957) also may have been responsible for the failure of the trout to respond to the presumed increase ill production of food. In view of the inconclusive circumstantial evidence, it be came of interest to attempt a direct measurement of production at the level of primary consumers. Measuring production of the planktonic Crustacea, the primary consumers, was made feasible with the help of 2 simplifications. It was assumed first, that all average standing crop was being re placed at a constant rate, and, second, that the rate of replacement of all species represented was approximately the rate of replacement of the dominant species. Because Daphnia dominated both portions of the lake, it was selected for this determination. The choice was facilitated by the fact that growth is proportional to the quantity of food available (Slobodkin 1954, 1959)

Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions

Objective. To describe prevalence, prenatal diagnosis and epidemiological data on oesophageal atresia from 23 well-defined European regions and compare the prevalence between these regions.Design. Population-based study using data from a large European database for surveillance of congenital anomalies (EUROCAT) for two decades (1987–2006).Settings. Twenty-three participating registries based on multiple sources of information including information about live births, fetal deaths with gestational age ?20 weeks and terminations of pregnancy.Patients. 1222 cases of oesophageal atresia in a population of 5019804 births.Results. The overall prevalence was 2.43 cases per 10 000 births (95% CI 2.30 to 2.57). There were regional differences in prevalence ranging from 1.27 to 4.55. Prenatal detection rates varied by registry from &gt;50% of cases to &lt;10% of cases. A total of 546 cases (44.7%) had an isolated oesophageal anomaly, 386 (31.6%) were multiple malformed and 290 (23.7%) had an association or a syndrome. There were 1084 live born cases (88.7%), 43 cases were fetal deaths and 95 cases were terminations of pregnancy. One-week survival for live births was 86.9% and 99.2% if the gestational age was ?38 weeks and isolated oesophageal atresia was present. Males accounted for 57.3% of all cases and 38.5% of live born cases were born with gestational age &lt;37 weeks.Conclusion. There were regional differences in prevalence of oesophageal atresia in Europe. Half of all cases had associated anomalies. Prenatal detection rate increased from 26% to 36.5% over the two decades. Survival in infants with isolated oesophageal atresia born at term is high

Incidence, Presentation and Outcome of Toxoplasmosis in HIV infected in the Combination Antiretroviral Therapy era

Background: HIV-associated incidence and prognosis of cerebral toxoplasmosis (CTX) is not well established during later years. Methods: From the Danish HIV Cohort Study, we identified 6325 HIV-infected individuals. We assessed incidence, mortality, predictive and prognostic factors of CTX during the pre-combination antiretroviral therapy (pre-cART; 1995-1996) and cART-era (1997-2014). Adjusted incidence rate ratios (aIRR), mortality rate ratios (aMRR) and 95% confidence intervals (CI) were assessed using Poisson regression analysis. Results: CTX IR was 1.17/1000 PYR (95% CI 0.93-1.47). We observed no change in CTX-risk in the first year after HIV-diagnosis, but a substantial reduction in mortality in the first 3 months after CTX diagnosis when comparing the cART-era to the pre-cART-era; ((aIRR: 0.79; 95% CI: 0.37-1.72) (aMRR: 0.15; 95% CI: 0.06-0.38)). For individuals surviving the first year after HIV-diagnosis or the first 3 months after CTX-diagnosis, IRR and MRR had declined to minimal levels ((aIRR: 0.06; 95% CI: 0.03-0.10); (aMRR: 0.02; 95% CI: 0.01-0.05)). Three years after CTX-diagnosis 30% of the patients still had neurological deficits. Conclusion: Although, CTX remains an important cause of morbidity and mortality in the cART-era, with high prevalence of neurological sequelae, incidence and mortality has largely declined, especially among those surviving the first year after diagnosis.</p

Incidence, clinical presentation, and outcome of hiv-1-associated cryptococcal meningitis during the highly active antiretroviral therapy era:A nationwide cohort study

Background: Human immunodeficiency virus (HIV) infection with advanced immunosup-pression predisposes to cryptococcal meningitis (CM). We describe the incidence, clinical presentation, and outcome of CM in HIV-infected individuals during the highly active antiretroviral therapy (HAART) era. Methods: A nationwide, population-based cohort of HIV-infected individuals was used to estimate incidence and mortality of CM including risk factors. A description of neurological symptoms of CM at presentation and follow-up in the study period 1995–2014 was included in this study. Results: Among 6,351 HIV-infected individuals, 40 were diagnosed with CM. The incidence rates were 3.7, 1.8, and 0.3 per 1000 person-years at risk in 1995–1996, 1997–1999, and 2000–2014, respectively. Initiation of HAART was associated with decreased risk of acquiring CM [incidence rate ratio (IRR), 0.1 (95% CI, 0.05–0.22)]. African origin was associated with increased risk of CM [IRR, 2.05 (95% CI, 1.00–4.20)]. The main signs and symptoms at presentation were headache, cognitive deficits, fever, neck stiffness, nausea, and vomiting. All individuals diagnosed with CM had a CD4 + cell count &lt;200 cells/µl [median 26; interquartile range (IQR), 10–50)]. Overall, mortality following CM was high and mortality in the first 4 months has not changed substantially over time. However, individuals who survived generally had a favorable prognosis, with 86% (18/21) returning to the pre-CM level of activity. Conclusion: The incidence of HIV-associated CM has decreased substantially after the introduction of HAART. To further decrease CM incidence and associated mortality, early HIV diagnosis and HAART initiation seems crucial.</p

Epidermal Acyl-CoA-binding protein is indispensable for systemic energy homeostasis

Objectives: The skin is the largest sensory organ of the human body and plays a fundamental role in regulating body temperature. However, adaptive alterations in skin functions and morphology have only vaguely been associated with physiological responses to cold stress or sensation of ambient temperatures. We previously found that loss of acyl-CoA-binding protein (ACBP) in keratinocytes upregulates lipolysis in white adipose tissue and alters hepatic lipid metabolism, suggesting a link between epidermal barrier functions and systemic energy metabolism. Methods: To assess the physiological responses to loss of ACBP in keratinocytes in detail, we used full-body ACBP−/− and skin-specific ACBP−/− knockout mice to clarify how loss of ACBP affects 1) energy expenditure by indirect calorimetry, 2) response to high-fat feeding and a high oral glucose load, and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). To further elucidate the role of the epidermal barrier in systemic energy metabolism, we included mice with defects in skin structural proteins (ma/ma Flgft/ft) in these studies. Results: We show that the ACBP−/− mice and skin-specific ACBP−/− knockout mice exhibited increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, was reversed by housing the mice at thermoneutrality (30 °C) or pharmacological β-adrenergic blocking. Interestingly, these findings were phenocopied in flaky tail mice (ma/ma Flgft/ft). Taken together, we demonstrate that a compromised epidermal barrier induces a β-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature. Conclusions: Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Thus, regulation of epidermal barrier functions warrants further attention to understand the regulation of systemic metabolism in further detail

Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy

OBJECTIVE: Ceramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy. METHODS: We used quantitative real-time PCR, Western blotting, and enzymatic assays to determine the mRNA, protein, and activity levels of ceramide synthase 2 (CERS2) in fiibroblasts isolated from parental control subjects and from a patient diagnosed with progressive myoclonic epilepsy (PME). Mass spectrometry and fluorescence microscopy were used to examine the effects of reduced CERS2 activity on cellular lipid composition and plasma membrane functions. RESULTS: We identify a novel 27 kb heterozygous deletion including the CERS2 gene in a proband diagnosed with PME. Compared to parental controls, levels of CERS2 mRNA, protein, and activity were reduced by ˜50% in fibroblasts isolated from this proband, resulting in significantly reduced levels of ceramides and sphingomyelins containing the very long-chain fatty acids C24:0 and C26:0. The change in SL composition was also reflected in a reduction in cholera toxin B immunofluorescence, indicating that membrane composition and function are altered. INTERPRETATION: We propose that reduced levels of CERS2, and consequently diminished levels of ceramides and SLs containing very long-chain fatty acids, lead to development of PME