The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy homeostasis and reproductive functions.

The orexigenic neurotransmitter neuropeptide Y (NPY) plays a central role in the hypothalamic control of food intake and energy balance. NPY also exerts an inhibition of the gonadotrope axis that could be important in the response to poor metabolic conditions. In contrast, leptin provides an anorexigenic signal to centrally control the body needs in energy. Moreover, leptin contributes to preserve adequate reproductive functions by stimulating the activity of the gonadotrope axis. It is of interest that hypothalamic NPY represents a primary target of leptin actions. To evaluate the importance of the NPY Y1 and Y5 receptors in the downstream pathways modulated by leptin and controlling energy metabolism as well as the activity of the gonadotrope axis, we studied the effects of leptin administration on food intake and reproductive functions in mice deficient for the expression of either the Y1 or the Y5 receptor. Furthermore, the role of the Y1 receptor in leptin resistance was determined in leptin-deficient ob/ob mice bearing a null mutation in the NPY Y1 locus. Results point to a crucial role for the NPY Y1 receptor in mediating the NPY pathways situated downstream of leptin actions and controlling food intake, the onset of puberty, and the maintenance of reproductive functions.

Separate neuronal and glial Na+,K+-ATPase isoforms regulate glucose utilization in response to membrane depolarization and elevated extracellular potassium.

The role of cell type-specific Na+,K+-ATPase isozymes in function-related glucose metabolism was studied using differentiated rat brain cell aggregate cultures. In mixed neuron-glia cultures, glucose utilization, determined by measuring the rate of radiolabeled 2-deoxyglucose accumulation, was markedly stimulated by the voltage-dependent sodium channel agonist veratridine (0.75 micromol/L), as well as by glutamate (100 micromol/L) and the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) (10 micromol/L). Significant stimulation also was elicited by elevated extracellular potassium (12 mmol/L KCl), which was even more pronounced at 30 mmol/L KCl. In neuron-enriched cultures, a similar stimulation of glucose utilization was obtained with veratridine, specific ionotropic glutamate receptor agonists, and 30 mmol/L but not 12 mmol/L KCl. The effects of veratridine, glutamate, and NMDA were blocked by specific antagonists (tetrodotoxin, CNQX, or MK801, respectively). Low concentrations of ouabain (10(-6) mol/L) prevented stimulation by the depolarizing agents but reduced only partially the response to 12 mmol/L KCl. Together with previous data showing cell type-specific expression of Na+,K+-ATPase subunit isoforms in these cultures, the current results support the view that distinct isoforms of Na+,K+-ATPase regulate glucose utilization in neurons in response to membrane depolarization, and in glial cells in response to elevated extracellular potassium.

Assessing the quality of alternative energy sources: Energy Return On the Investment (EROI), the metabolic pattern of societies and energy statistics

This paper presents an initial challenge to tackle the every so "tricky" points encountered when dealing with energy accounting, and thereafter illustrates how such a system of accounting can be used when assessing for the metabolic changes in societies. The paper is divided in four main sections. The first three, present a general discussion on the main issues encountered when conducting energy analyses. The last section, subsequently, combines this heuristic approach to the actual formalization of it, in quantitative terms, for the analysis of possible energy scenarios. Section one covers the broader issue of how to account for the relevant categories used when accounting for Joules of energy; emphasizing on the clear distinction between Primary Energy Sources (PES) (which are the physical exploited entities that are used to derive useable energy forms (energy carriers)) and Energy Carriers (EC) (the actual useful energy that is transmitted for the appropriate end uses within a society). Section two sheds light on the concept of Energy Return on Investment (EROI). Here, it is emphasized that, there must already be a certain amount of energy carriers available to be able to extract/exploit Primary Energy Sources to thereafter generate a net supply of energy carriers. It is pointed out that this current trend of intense energy supply has only been possible to the great use and dependence on fossil energy. Section three follows up on the discussion of EROI, indicating that a single numeric indicator such as an output/input ratio is not sufficient in assessing for the performance of energetic systems. Rather an integrated approach that incorporates (i) how big the net supply of Joules of EC can be, given an amount of extracted PES (the external constraints); (ii) how much EC needs to be invested to extract an amount of PES; and (iii) the power level that it takes for both processes to succeed, is underlined. Section four, ultimately, puts the theoretical concepts at play, assessing for how the metabolic performances of societies can be accounted for within this analytical framework.

Nutrition and acute schistosomiasis

In northeast Brazil, nutritional deficiency diseases and schistosomiasis mansoni overlap. An experimental model, wich reproduces the marasmatic clinical form of protein-energy malnutrition, was developed in this laboratory to study these interactions. Albino Swiss mice were fed with a food association ingested usually by human populations in northeast Brazil. This diet (Regional Basic Diet - RBD) has negative effects on the growth, food intake and protein utilization in infected mice (acute phase of murine schistosomiasis). Nitrogen balance studies have also shown that infection with Schistosoma mansoni has apparently no effect on protein intestinal absorption in well nourished mice. However, the lowest absorption ratios have been detected among RBD - fed infected animals, suggesting that suprerimposed schistosome infection aggravated the nutritional status of the undernourished host. The serum proteins electrophoretic pattern, as far as albumins are concerned, is quite similar for non-infected undernourished and infected well-fed animals. So, the significance of albumins as a biochemical indicator of the nutritional status of human populations residing in endemic foci of Manson's schistosomiasis, is discussable.

Pregnancy-related changes in activity energy expenditure and resting metabolic rate in Switzerland.

BACKGROUND/OBJECTIVES: To measure resting metabolic rate (RMR), activity energy expenditure (AEE), total energy expenditure (TEE) and physical activity pattern, that is, duration and intensity (in metabolic equivalents, METs) of activities performed in late pregnancy compared with postpartum in healthy, well-nourished women living in Switzerland. SUBJECTS/METHODS: Weight, height, RMR, AEE, TEE and physical activity patterns were measured longitudinally in 27 healthy women aged 23-40 years at 38.2+/-1.5 weeks of gestation and 40.0+/-7.2 weeks postpartum. RESULTS: The RMR during late pregnancy was 7480 kJ per day, that is, 1320+/-760 kJ per day (21.4%) higher than the postpartum RMR (P<0.001). Absolute changes in RMR were positively correlated with the corresponding changes in body weight (r=0.61, P<0.001). RMR per kg body weight was similar in late pregnancy vs postpartum (P=0.28). AEE per kg during pregnancy and postpartum was 40+/-13 and 50+/-20 kJ/kg, respectively (P=0.001). There were significant differences in daily time spent at METs<1.5 (1067 vs 998 min, P=0.045), at 2.5< or =METs <3.0 (58 vs 82 min, P=0.002) and METs> or =6 (1 vs 6 min, P=0.014) during pregnancy and postpartum, respectively. CONCLUSIONS: Energy expenditure in healthy women living in Switzerland increases in pregnancy compared with the postpartum state. Additional energy expenditure is primarily attributed to an increase in RMR, which is partly compensated by a decrease in AEE. The decrease in physical activity-related energy costs is achieved by selecting less demanding activities and should be taken into account when defining extra energy requirements for late pregnancy in Switzerland.

Twenty-four-hour energy expenditure and thermogenesis: response to progressive carbohydrate overfeeding in man.

Short-term overfeeding with carbohydrate induced a marked stimulation of energy expenditure, amounting to 33 per cent of the excess energy intake on the 7th day of overfeeding. This value is larger than that previously reported in man. Stimulation of lipogenesis and increased activity of the sympathetic nervous system seem to be the two major mechanisms which account for the stimulation of energy expenditure during carbohydrate overfeeding.

Energy expenditure by doubly labeled water: validation in humans and proposed calculation.

To further validate the doubly labeled water method for measurement of CO2 production and energy expenditure in humans, we compared it with near-continuous respiratory gas exchange in nine healthy young adult males. Subjects were housed in a respiratory chamber for 4 days. Each received 2H2(18)O at either a low (n = 6) or a moderate (n = 3) isotope dose. Low and moderate doses produced initial 2H enrichments of 5 and 10 X 10(-3) atom percent excess, respectively, and initial 18O enrichments of 2 and 2.5 X 10(-2) atom percent excess, respectively. Total body water was calculated from isotope dilution in saliva collected at 4 and 5 h after the dose. CO2 production was calculated by the two-point method using the isotopic enrichments of urines collected just before each subject entered and left the chamber. Isotope enrichments relative to predose samples were measured by isotope ratio mass spectrometry. At low isotope dose, doubly labeled water overestimated average daily energy expenditure by 8 +/- 9% (SD) (range -7 to 22%). At moderate dose the difference was reduced to +4 +/- 5% (range 0-9%). The isotope elimination curves for 2H and 18O from serial urines collected from one of the subjects showed expected diurnal variations but were otherwise quite smooth. The overestimate may be due to approximations in the corrections for isotope fractionation and isotope dilution. An alternative approach to the corrections is presented that reduces the overestimate to 1%.

The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms.

Background: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferatoractivated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.Objectives: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.Methods: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.Results: DEHP-treated mice were protected from diet-induced obesity via PPARalpha-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARbeta nor PPARgamma was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARalpha-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.Conclusion: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARalpha signaling and highlight the metabolic importance of the species-specific activation of PPARalpha by xenobiotic compounds. Editor's SummaryDiethylhexyl phthalate (DEHP) is an industrial plasticizer used in cosmetics, medical devices, food packaging, and other applications. Evidence that DEHP metabolites can activate peroxisome proliferatoractivated receptors (PPARs) involved in fatty acid oxidation (PPARalpha and PPARbeta) and adiposite function and insulin resistance (PPARgamma) has raised concerns about potential effects of DEHP on metabolic homeostasis. In rodents, PPARalpha activation also induces hepatic peroxisome proliferation, but this response to PPARalpha activation is not observed in humans. Feige et al. (p. 234) evaluated systemic and metabolic consequences of high-dose oral DEHP in combination with a high-fat diet in wild-type mice and genetically engineered mouse PPAR models. The authors report that mice exposed to DEHP gained less weight than controls, without modifying their feeding behavior; they also exhibited lower triglyceride levels, smaller adipocytes, and improved glucose tolerance compared with controls. These effects, which were observed in mice fed both high-fat and standard diets, appeared to be mediated by PPARalpha-dependent activation of hepatic fatty acid catabolism without apparent involvement of PPARbeta or PPARgamma. However, mouse models that expressed human (versus mouse) PPARalpha tended to gain more weight on a high-fat diet than their DHEP-unexposed counterparts. The authors conclude that findings support species-specific metabolic effects of DEHP mediated by PPARalpha activation.

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.

Going beyond energy intensity to understand the energy metabolism of nations: the case of Argentina

The link between energy consumption and economic growth has been widely studied in the economic literature. Understanding this relationship is important from both an environmental and a socio-economic point of view, as energy consumption is crucial to economic activity and human environmental impact. This relevance is even higher for developing countries, since energy consumption per unit of output varies through the phases of development, increasing from an agricultural stage to an industrial one and then decreasing for certain service based economies. In the Argentinean case, the relevance of energy consumption to economic development seems to be particularly important. While energy intensity seems to exhibit a U-Shaped curve from 1990 to 2003 decreasing slightly after that year, total energy consumption increases along the period of analysis. Why does this happen? How can we relate this result with the sustainability debate? All these questions are very important due to Argentinean hydrocarbons dependence and due to the recent reduction in oil and natural gas reserves, which can lead to a lack of security of supply. In this paper we study Argentinean energy consumption pattern for the period 1990-2007, to discuss current and future energy and economic sustainability. To this purpose, we developed a conventional analysis, studying energy intensity, and a non conventional analysis, using the Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM) accounting methodology. Both methodologies show that the development process followed by Argentina has not been good enough to assure sustainability in the long term. Instead of improving energy use, energy intensity has increased. The current composition of its energy mix, and the recent economic crisis in Argentina, as well as its development path, are some of the possible explanations.