Resting metabolic rate and protein turnover in apparently healthy elderly Gambian men.

Body composition, resting energy expenditure (REE), and whole body protein metabolism were studied in 26 young and 28 elderly Gambian men matched for body mass index during the dry season in a rural village in The Gambia. REE was measured by indirect calorimetry (hood system) in the fasting state and after five successive meals. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotopic enrichment of urinary ammonia over a period of 12 h after a single oral dose of [15N]glycine. Expressed in absolute value, REE was significantly lower in the elderly compared with the young group (3.21 +/- 0.07 vs. 4.04 +/- 0.07 kJ/min, P < 0.001) and when adjusted to body weight (3.29 +/- 0.05 vs. 3.96 +/- 0.05 kJ/min, P < 0.0001) and fat-free mass (FFM; 3.38 +/- 0.01 vs. 3.87 +/- 0.01 kJ/min, P < 0.0001). The rate of protein synthesis averaged 207 +/- 13 g protein/day in the elderly and 230 +/- 13 g protein/day in the young group, whereas protein breakdown averaged 184 +/- 13 g protein/day in the elderly and 203 +/- 13 g protein/day in the young group (nonsignificant). When values were adjusted for body weight or FFM, they did not reveal any difference between the two groups. It is concluded that the reduced REE adjusted for body composition observed in elderly Gambian men is not explained by a decrease in protein turnover.

High fat versus high carbohydrate nutritional supplementation: a one year trial in stunted rural Gambian children.

OBJECTIVE: The study tests the hypothesis that a low daily fat intake may induce a negative fat balance and impair catch-up growth in stunted children between 3 and 9y of age. DESIGN: Randomized case-control study. SETTING: Three rural villages of the West Kiang District, The Gambia. SUBJECTS: Three groups of 30 stunted but not wasted children (height for age z-score < or = -2.0, weight for height z-score > or = -2.0) 3-9 y of age were selected by anthropometric survey. Groups were matched for age, sex, village, degree of stunting and season. INTERVENTION: Two groups were randomly assigned to be supplemented five days a week for one year with either a high fat (n = 29) or a high carbohydrate biscuit (n = 30) each containing approximately 1600 kJ. The third group was a non supplemented control group (n = 29). Growth, nutritional status, dietary intake, resting energy expenditure and morbidity were compared. RESULTS: Neither the high fat nor the high carbohydrate supplement had an effect on weight or height gain. The high fat supplement did slightly increase adipose tissue mass. There was no effect of supplementation on resting energy expenditure or morbidity. In addition, the annual growth rate was not associated with a morbidity score. CONCLUSIONS: Results show that neither a high fat nor a high carbohydrate supplement given during 12 months to stunted Gambian children induced catch-up growth. The authors suggest that an adverse effect of the environment on catch-up growth persists despite the nutritional interventions.

Serum Leptin Concentration, Body Mass Index and Incident Heart Failure: The Health, Aging, and Body Composition Study

Background: Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important factor for congestive heart faire (CHF). In the study, we aimed to test the hypothesis that leptin may influence CHF pathophysiology via a pathway of increasing body mass index (BMI). Methods: We studied 2,389 elderly participants aged 70 and older (M; 1161, F: 1228) without CHF and with serum leptin measures at the Health Aging, and Body Composition study. We analyzed the association between serum leptin level and risk of incident CHF using Cox hazard proportional regression models. Elevated leptin level was defined as more than the highest quartile (Q4) of leptin distribution in the total sample for each gender. Adjusted-covariates included demographic, behavior, lipid and inflammation variables (partially-adjusted models), and further included BMI (fully-adjusted models). Results: In a mean 9-year follow-up, 316 participants (13.2%) developed CHF. The partially-adjusted models indicated that men and women with elevated serum leptin levels (>=9.89 ng/ml in men and >=25 ng/ml in women) had significantly higher risks of developing CHF than those with leptin level of less than Q4. The adjusted hazard ratios (95%CI) for incident CHF was 1.49 (1.04 -2.13) in men and 1.71 (1.12 -2.58) in women. However, these associations became non-significant after adjustment for including BMI for each gender. The fully-adjusted hazard ratios (95%CI) were 1.43 (0.94 -2.18) in men and 1.24 (0.77-1.99) in women. Conclusion: Subjects with elevated leptin levels have a higher risk of CHF. The study supports the hypothesis that the influence of leptin level on risk of CHF may be through a pathway related to increasing BMI.

Measurement of 13CO2 in expired air as an index of compliance to a high carbohydrate diet naturally enriched in 13C.

The aim of this study was to determine whether breath 13CO2 measurements could be used to assess the compliance to a diet containing carbohydrates naturally enriched in 13C. The study was divided into two periods: Period 1 (baseline of 4 days) with low 13C/12C ratio carbohydrates. Period 2 (5 days) isocaloric diet with a high 13C/12C ratio (corn, cane sugar, pineapple, millet) carbohydrates. Measurements were made of respiratory gas exchange by indirect calorimetry, urinary nitrogen excretion and breath 13CO2 every morning in post-absorptive conditions, both in resting state and during a 45-min low intensity exercise (walking on a treadmill). The subjects were 10 healthy lean women (BMI 20.4 +/- 1.7 kg/m2, % body fat 24.4 +/- 1.3%), the 13C enrichment of oxidized carbohydrate and breath 13CO2 were compared to the enrichment of exogenous dietary carbohydrates. At rest the enrichment of oxidized carbohydrate increased significantly after one day of 13C carbohydrate enriched diet and reached a steady value (103 +/- 16%) similar to the enrichment of exogenous carbohydrates. During exercise, the 13C enrichment of oxidized carbohydrate remained significantly lower (68 +/- 17%) than that of dietary carbohydrates. The compliance to a diet with a high content of carbohydrates naturally enriched in 13C may be assessed from the measurement of breath 13CO2 enrichment combined with respiratory gas exchange in resting, postabsorptive conditions.

Consequences of smoking for body weight, body fat distribution, and insulin resistance

Our aim was to critically evaluate the relations among smoking, body weight, body fat distribution, and insulin resistance as reported in the literature. In the short term, nicotine increases energy expenditure and could reduce appetite, which may explain why smokers tend to have lower body weight than do nonsmokers and why smoking cessation is frequently followed by weight gain. In contrast, heavy smokers tend to have greater body weight than do light smokers or nonsmokers, which likely reflects a clustering of risky behaviors (eg, low degree of physical activity, poor diet, and smoking) that is conducive to weight gain. Other factors, such as weight cycling, could also be involved. In addition, smoking increases insulin resistance and is associated with central fat accumulation. As a result, smoking increases the risk of metabolic syndrome and diabetes, and these factors increase risk of cardiovascular disease. In the context of the worldwide obesity epidemic and a high prevalence of smoking, the greater risk of (central) obesity and insulin resistance among smokers is a matter of major concern

HCV infection induces mitochondrial bioenergetic unbalance: causes and effects.

Cells infected by the hepatitis C virus (HCV) are characterized by endoplasmic reticulum stress, deregulation of the calcium homeostasis and unbalance of the oxido-reduction state. In this context, mitochondrial dysfunction proved to be involved and is thought to contribute to the outcome of the HCV-related disease. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This causes successive mitochondrial alterations comprising generation of reactive oxygen and nitrogen species and impairment of the oxidative phosphorylation. A progressive adaptive response results in an enhancement of the glycolytic metabolism sustained by up-regulation of the hypoxia inducible factor. Pathogenetic implications of the model are discussed.

Are glutamate and lactate increases ubiquitous to physiological activation? A (1)H functional MR spectroscopy study during motor activation in human brain at 7Tesla.

Recent studies at high field (7Tesla) have reported small metabolite changes, in particular lactate and glutamate (below 0.3μmol/g) during visual stimulation. These studies have been limited to the visual cortex because of its high energy metabolism and good magnetic resonance spectroscopy (MRS) sensitivity using surface coil. The aim of this study was to extend functional MRS (fMRS) to investigate for the first time the metabolite changes during motor activation at 7T. Small but sustained increases in lactate (0.17μmol/g±0.05μmol/g, p<0.001) and glutamate (0.17μmol/g±0.09μmol/g, p<0.005) were detected during motor activation followed by a return to the baseline after the end of activation. The present study demonstrates that increases in lactate and glutamate during motor stimulation are small, but similar to those observed during visual stimulation. From the observed glutamate and lactate increase, we inferred that these metabolite changes may be a general manifestation of the increased neuronal activity. In addition, we propose that the measured metabolite concentration increases imply an increase in ΔCMRO2 that is transiently below that of ΔCMRGlc during the first 1 to 2min of the stimulation.

Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection.

Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor approximately 18-25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.

Current Molecular Imaging of Spinal Tumors in Clinical Practice.

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.

Efficient gene delivery and selective transduction of astrocytes in the mammalian brain using viral vectors.

Astrocytes are now considered as key players in brain information processing because of their newly discovered roles in synapse formation and plasticity, energy metabolism and blood flow regulation. However, our understanding of astrocyte function is still fragmented compared to other brain cell types. A better appreciation of the biology of astrocytes requires the development of tools to generate animal models in which astrocyte-specific proteins and pathways can be manipulated. In addition, it is becoming increasingly evident that astrocytes are also important players in many neurological disorders. Targeted modulation of protein expression in astrocytes would be critical for the development of new therapeutic strategies. Gene transfer is valuable to target a subpopulation of cells and explore their function in experimental models. In particular, viral-mediated gene transfer provides a rapid, highly flexible and cost-effective, in vivo paradigm to study the impact of genes of interest during central nervous system development or in adult animals. We will review the different strategies that led to the recent development of efficient viral vectors that can be successfully used to selectively transduce astrocytes in the mammalian brain.

Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway.

Lactate is increasingly described as an energy substrate of the brain. Beside this still debated metabolic role, lactate may have other effects on brain cells. Here, we describe lactate as a neuromodulator, able to influence the activity of cortical neurons. Neuronal excitability of mouse primary neurons was monitored by calcium imaging. When applied in conjunction with glucose, lactate induced a decrease in the spontaneous calcium spiking frequency of neurons. The effect was reversible and concentration dependent (IC50 ∼4.2 mM). To test whether lactate effects are dependent on energy metabolism, we applied the closely related substrate pyruvate (5 mM) or switched to different glucose concentrations (0.5 or 10 mM). None of these conditions reproduced the effect of lactate. Recently, a Gi protein-coupled receptor for lactate called HCA1 has been introduced. To test if this receptor is implicated in the observed lactate sensitivity, we incubated cells with pertussis toxin (PTX) an inhibitor of Gi-protein. PTX prevented the decrease of neuronal activity by L-lactate. Moreover 3,5-dyhydroxybenzoic acid, a specific agonist of the HCA1 receptor, mimicked the action of lactate. This study indicates that lactate operates a negative feedback on neuronal activity by a receptor-mediated mechanism, independent from its intracellular metabolism.

Failure of dietary fat intake to promote fat oxidation: a factor favoring the development of obesity.

Seven young men spent three nights and 2 d in a respiration chamber where their rates of energy expenditure and substrate oxidation were continuously measured by indirect calorimetry. During the first 24 h they ingested a mixed maintenance diet containing 35% of calories as fat. An additional amount of 106 +/- 6 g fat/24 h (means +/- SD) was added to this diet during the following 36 h. The fat supplement (987 +/- 55 kcal/d) did not alter 24-h energy expenditure (2783 +/- 232 vs 2820 +/- 284 kcal/d) and failed to promote the use of fat as a metabolic fuel (fat oxidation 1032 +/- 205 vs 1042 +/- 205 kcal/d). The overall energy balance was closely correlated with the fat balance (r = 0.96, p less than 0.001) but not with the carbohydrate balance (r = -0.12, NS). These data indicate that substantial imbalances between intake and oxidation are much more likely for fat than for carbohydrate.

Lack of metabolic and behavioral adaptations in rural Gambian men with low body mass index.

Energy expenditure was measured by means of a respiratory chamber in two groups of adult rural Gambian men. The first group (n = 29) had a low body mass index (BMI; in kg/m2) < 18.5), whereas the control group (n = 29) had a higher BMI (> 22). This study shows that the energy expenditure of Gambian men with low BMI is not different from that of Gambian men with normal BMI when the results are normalized for fat-free mass or for weight by analysis of covariance. In Gambian men the nutritional status thus does not seem to affect energy metabolism notably. No differences in respiratory quotient, diet-induced thermogenesis, net work efficiency, spontaneous physical activity, heart rate, or urinary catecholamine excretion were observed between the two groups. It is, however, interesting to note that the basal metabolic rate of Gambian men, regardless of their nutritional status, is approximately 10% (range 4-12% depending on the reference value used) lower than that predicted for individuals living in industrialized countries.

Thermogenic effect of amrinone in healthy men.

OBJECTIVES: The thermogenic effect of amrinone is unknown and its utilization in patients with severe cardiac failure could potentially increase oxygen requirements and therefore aggravate oxygen debt. Consequently, the present study was undertaken to assess the thermogenic response to amrinone at three different plasma concentrations under controlled conditions and to analyze amrinone's effects on various biochemical variables. DESIGN: A prospective, unblinded, controlled study. The initial control period was followed by three sequential, experimental treatments. SUBJECTS: Ten young, healthy, male volunteers with normal body weight. INTERVENTIONS: Three experimental periods. Amrinone was administered intravenously in progressive doses: a) 0.5 mg/kg followed by 5 micrograms/kg/min; b) 0.5 mg/kg followed by 10 micrograms/kg/min; and c) 1.0 mg/kg followed by 10 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2) and CO2 production were continuously measured by means of a computerized indirect calorimeter. At the highest dose, amrinone produced a slight and significant (p < .01) increase in VO2 and in resting metabolic rate (+4.5% and +3.7%, respectively), while no change in CO2 production or in respiratory quotient occurred throughout the study. At the medium and high doses, amrinone increased plasma free fatty acid concentrations by 38% and 53%, respectively (p < .05). No variation in plasma glucose, lactate, insulin, norepinephrine, or epinephrine concentrations was observed during the study. CONCLUSIONS: Amrinone administered intravenously at therapeutic doses has minimal thermogenic and metabolic effects in humans without cardiac failure.

Effect of diets high or low in unavailable and slowly digestible carbohydrates on the pattern of 24-h substrate oxidation and feelings of hunger in humans.

BACKGROUND: The pattern of substrate utilization with diets containing a high or a low proportion of unavailable and slowly digestible carbohydrates may constitute an important factor in the control, time course, and onset of hunger in humans. OBJECTIVE: We tested the hypothesis that isoenergetic diets differing only in their content of unavailable carbohydrates would result in different time courses of total, endogenous, and exogenous carbohydrate oxidation rates. DESIGN: Two diets with either a high (H diet) or a low (L diet) content of unavailable carbohydrates were fed to 14 healthy subjects studied during two 24-h periods in a metabolic chamber. Substrate utilization was assessed by whole-body indirect calorimetry. In a subgroup of 8 subjects, endogenous and exogenous carbohydrate oxidation were assessed by prelabeling the body glycogen stores with [(13)C]carbohydrate. Subjective feelings of hunger were estimated with use of visual analogue scales. RESULTS: Total energy expenditure and substrate oxidation did not differ significantly between the 2 diets. However, there was a significant effect of diet (P: = 0.03) on the carbohydrate oxidation pattern: the H diet elicited a lower and delayed rise of postprandial carbohydrate oxidation and was associated with lower hunger feelings than was the L diet. The differences in hunger scores between the 2 diets were significantly associated with the differences in the pattern of carbohydrate oxidation among diets (r = -0.67, P: = 0. 006). Exogenous and endogenous carbohydrate oxidation were not significantly influenced by diet. CONCLUSIONS: The pattern of carbohydrate utilization is involved in the modulation of hunger feelings. The greater suppression of hunger after the H diet than after the L diet may be helpful, at least over the short term, in individuals attempting to better control their food intake.