Courtney M. Peterson

Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.

Skeletal Muscle Mitochondria and Aging: A Review

Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline.

Sphingosine-1-phosphate and lipid phosphohydrolases

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts as both an extracellular ligand for the endothelial differentiation gene-1 (EDG-1) G-protein coupled receptor (GPCR) family and as an intracellular messenger. Cellular levels of S1P are low and tightly regulated in a spatial-temporal manner not only by sphingosine kinase (SPHK) but also by degradation catalyzed by S1P lyase, specific S1P phosphohydrolases, and by general lipid phosphate phosphohydrolases (LPPs). LPPs are characterized as magnesium-independent, insensitive to inhibition by N-ethylmaleimide (NEM) and possessing broad substrate specificity with a variety of phosphorylated lipids, including S1P, phosphatidic acid (PA), and lysophosphatidic acid (LPA). LPPs contain three highly conserved domains that define a phosphohydrolase superfamily. Recently, several specific S1P phosphohydrolases have been identified in yeast and mammalian cells. Phylogenetic and biochemical analyses indicate that these enzymes constitute a new subset of the LPP family. As further evidence, S1P phosphohydrolases exhibit high specificity for phosphorylated sphingoid bases. Enforced expression of S1P phosphohydrolase alters the cellular levels of sphingolipid metabolites in yeast and mammalian cells, increasing sphingosine and ceramide, bioactive sphingolipids that often have opposing biological actions to S1P. By regulating the cellular ratio between ceramide/sphingosine and S1P, S1P phosphohydrolase is poised to be a critical factor in cell survival/cell death decisions. Indeed, expression of S1P phosphohydrolase in mammalian cells increases apoptosis, whereas deletion of S1P phosphohydrolases in yeast correlates with resistance to heat stress. In this review, we discuss the role of phosphohydrolases in the metabolism of S1P and how turnover of S1P can regulate sphingolipid metabolites signaling.

Evolving Concepts on Adjusting Human Resting Energy Expenditure Measurements for Body Size

Establishing if an adults resting energy expenditure (REE) is high or low for their body size is a pervasive question in nutrition research. Early workers applied body mass and height as size measures and formulated the Surface Law and Kleibers Law, although each has limitations when adjusting REE. Body composition methods introduced during the mid‐20th century provided a new opportunity to identify metabolically homogeneous ‘active’ compartments. These compartments all show improved correlations with REE estimates over body mass–height approaches, but collectively share a common limitation: REE‐body composition ratios are not ‘constant’ but vary across men and women and with race, age and body size. The now‐accepted alternative to ratio‐based norms is to adjust for predictors by applying regression models to calculate ‘residuals’ that establish if an REE is relatively high or low. The distinguishing feature of statistical REE‐body composition models is a ‘non‐zero’ intercept of unknown origin. The recent introduction of imaging methods has allowed development of physiological tissue–organ‐based REE prediction models. Herein, we apply these imaging methods to provide a mechanistic explanation, supported by experimental data, for the non‐zero intercept phenomenon and, in that context, propose future research directions for establishing between‐subject differences in relative energy metabolism.

Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model.

To develop a new geometrical index that combines height, waist circumference (WC), and hip circumference (HC) and relate this index to total and visceral body fat.

Why are there race/ethnic differences in adult body mass index-adiposity relationships? A quantitative critical review.

Body mass index (BMI) is now the most widely used measure of adiposity on a global scale. Nevertheless, intense discussion centers on the appropriateness of BMI as a phenotypic marker of adiposity across populations differing in race and ethnicity. BMI–adiposity relations appear to vary significantly across race/ethnic groups, but a collective critical analysis of these effects establishing their magnitude and underlying body shape/composition basis is lacking. Accordingly, we systematically review the magnitude of these race‐ethnic differences across non‐Hispanic (NH) white, NH black and Mexican American adults, their anatomic body composition basis and potential biologically linked mechanisms, using both earlier publications and new analyses from the US National Health and Nutrition Examination Survey. Our collective observations provide a new framework for critically evaluating the quantitative relations between BMI and adiposity across groups differing in race and ethnicity; reveal new insights into BMI as a measure of adiposity across the adult age‐span; identify knowledge gaps that can form the basis of future research and create a quantitative foundation for developing BMI‐related public health recommendations.

Resveratrol vs. calorie restriction: data from rodents to humans.

Calorie restriction extends lifespan and confers metabolic benefits similar to the effect of lifestyle interventions. Poor compliance to long-term dietary restriction, however, hinders the success of this approach. Evidence is now persuasive for a role of resveratrol supplementation (a polyphenol in red grapes) as potential alternative to calorie restriction. This review summarizes the latest literature on the effects and the molecular mechanisms by which calorie restriction and resveratrol confer health benefits. Resveratrol activates SIRT1 and the associated improvement in energy utilization and insulin sensitivity closely resembles the benefits of calorie restriction. Current data largely support resveratrol as a potential calorie restriction mimetic to improve metabolic and probably functional health. Future studies which characterize the bioavailability and efficacy of resveratrol supplementation are critical to provide evidence for its long-term health benefits.

Non-Gaussianity in two-field inflation

We derive semi-analytic formulae for the local bispectrum and trispectrum in general two-field inflation and provide a simple geometric recipe for building observationally allowed models with observable non-Gaussianity. We use the \delta N formalism and the transfer function formalism to express the bispectrum almost entirely in terms of model-independent physical quantities. Similarly, we calculate the trispectrum and show that the trispectrum parameter \tau NL can be expressed entirely in terms of spectral observables, which provides a new consistency relation unique to two-field inflation. We show that in order to generate observably large non-Gaussianity during inflation, the sourcing of curvature modes by isocurvature modes must be extremely sensitive to the initial conditions, and that the amount of sourcing must be moderate in order to avoid excessive fine-tuning. Under some minimal assumptions, we argue that the first condition is satisfied only when neighboring trajectories through the two-dimensional field space diverge during inflation. Geometrically, this means that the inflaton must roll along a ridge in the potential V for some time during inflation and that its trajectory must turn slightly (but not too sharply) in field space. Therefore, it follows that two-field scenarios with attractor solutions necessarily produce small non-Gaussianity. This explains why it has been so difficult to achieve large non-Gaussianity in two-field inflation, and why it has only been achieved in a narrow class of models like hybrid inflation and certain product potentials where the potential and/or the initial conditions are fine-tuned. Some of our conclusions generalize qualitatively to general multi-field inflation.

MITEoR: a scalable interferometer for precision 21 cm cosmology

We report on the MIT Epoch of Reionization (MITEoR) experiment, a pathfinder low-frequency radio interferometer whose goal is to test technologies that improve the calibration precision and reduce the cost of the high-sensitivity 3D mapping required for 21 cm cosmology. MITEoR accomplishes this by using massive baseline redundancy, which enables both automated precision calibration and correlator cost reduction. We demonstrate and quantify the power and robustness of redundancy for scalability and precision. We find that the calibration parameters precisely describe the effect of the instrument upon our measurements, allowing us to form a model that is consistent with

Scaling of adult body weight to height across sex and race/ethnic groups: relevance to BMI

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