On optimal computation of MPLS label binding for multipoint-to-point connections

Most network operators have considered reducing Label Switched Routers (LSR) label spaces (i.e. the number of labels that can be used) as a means of simplifying management of underlaying Virtual Private Networks (VPNs) and, hence, reducing operational expenditure (OPEX). This letter discusses the problem of reducing the label spaces in Multiprotocol Label Switched (MPLS) networks using label merging - better known as MultiPoint-to-Point (MP2P) connections. Because of its origins in IP, MP2P connections have been considered to have tree- shapes with Label Switched Paths (LSP) as branches. Due to this fact, previous works by many authors affirm that the problem of minimizing the label space using MP2P in MPLS - the Merging Problem - cannot be solved optimally with a polynomial algorithm (NP-complete), since it involves a hard- decision problem. However, in this letter, the Merging Problem is analyzed, from the perspective of MPLS, and it is deduced that tree-shapes in MP2P connections are irrelevant. By overriding this tree-shape consideration, it is possible to perform label merging in polynomial time. Based on how MPLS signaling works, this letter proposes an algorithm to compute the minimum number of labels using label merging: the Full Label Merging algorithm. As conclusion, we reclassify the Merging Problem as Polynomial-solvable, instead of NP-complete. In addition, simulation experiments confirm that without the tree-branch selection problem, more labels can be reduced

Label Space Reduction in MPLS Networks: How Much Can A Single Stacked Label Do?

Most network operators have considered reducing LSR label spaces (number of labels used) as a way of simplifying management of underlaying virtual private networks (VPNs) and therefore reducing operational expenditure (OPEX). The IETF outlined the label merging feature in MPLS-allowing the configuration of multipoint-to-point connections (MP2P)-as a means of reducing label space in LSRs. We found two main drawbacks in this label space reduction a)it should be separately applied to a set of LSPs with the same egress LSR-which decreases the options for better reductions, and b)LSRs close to the edge of the network experience a greater label space reduction than those close to the core. The later implies that MP2P connections reduce the number of labels asymmetrically

Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus SEMICYUC-SENPE: Obese patient

As a response to metabolic stress, obese critically-ill patients have the same risk of nutritional deficiency as the non-obese and can develop protein-energy malnutrition with accelerated loss of muscle mass. The primary aim of nutritional support in these patients should be to minimize loss of lean mass and accurately evaluate energy expenditure. However, routinely used formulae can overestimate calorie requirements if the patient's actual weight is used. Consequently, the use of adjusted or ideal weight is recommended with these formulae, although indirect calorimetry is the method of choice. Controversy surrounds the question of whether a strict nutritional support criterion, adjusted to the patient's requirements, should be applied or whether a certain degree of hyponutrition should be allowed. Current evidence suggested that hypocaloric nutrition can improve results, partly due to a lower rate of infectious complications and better control of hyperglycemia. Therefore, hypocaloric and hyperproteic nutrition, whether enteral or parenteral, should be standard practice in the nutritional support of critically-ill obese patients when not contraindicated. Widely accepted recommendations consist of no more than 60-70% of requirements or administration of 11-14 kcal/kg current body weight/day or 22-25 kcal/kg ideal weight/day, with 2-2.5 g/kg ideal weight/day of proteins. In a broad sense, hypocaloric-hyperprotein regimens can be considered specific to obese critically-ill patients, although the complications related to comorbidities in these patients may require other therapeutic possibilities to be considered, with specific nutrients for hyperglycemia, acute respiratory distress syndrome (ARDS) and sepsis. However, there are no prospective randomized trials with this type of nutrition in this specific population subgroup and the available data are drawn from the general population of critically-ill patients. Consequently, caution should be exercised when interpreting these data.

Influences of body weight, body composition, and substrate oxidation rate on resting postabsorptive glucose production and gluconeogenesis.

OBJECTIVE: To determine the influence of body weight, fat mass, and fat distribution on resting endogenous glucose production in healthy lean and overweight individuals. DESIGN: measurements were performed in the resting postabsorptive state in individuals receiving an unrestricted diet. SETTING: Institute of Physiology of Lausanne University. MEASUREMENTS: resting post absorptive glucose production, glycogenolysis and gluconeogenesis; resting energy expenditure and net substrate oxidation. RESULTS: Endogenous glucose production was positively correlated with body weight, lean body mass, energy expenditure and carbohydrate oxidation. Gluconeogenesis was positively correlated with net lipid oxidation and energy expenditure, and negatively correlated with net carbohydrate oxidation. No correlation with body fat or fat distribution was observed. CONCLUSIONS: Gluconeogenesis shows a large interindividual variability. Net lipid oxidation and not body fat appears to be a major determinant of gluconeogenesis.

Topics in public finance: social security and taxation

Summary The field of public finance focuses on the spending and taxing activities of governments and their influence on the allocation of resources and distribution of income. This work covers in three parts different topics related to public finance which are currently widely discussed in media and politics. The first two parts deal with issues on social security, which is in general one of the biggest spending shares of governments. The third part looks at the main income source of governments by analyzing the perceived value of tax competition. Part one deals with the current problem of increased early retirement by focusing on Switzerland as a special case. Early retirement is predominantly considered to be the result of incentives set by social security and the tax system. But the Swiss example demonstrates that the incidence of early retirement has dramatically increased even in the absence of institutional changes. We argue that the wealth effect also plays an important role in the retirement decision for middle and high income earners. An actuarially fair, but mandatory funded system with a relatively high replacement rate may thus contribute to a low labor market participation rate of elderly workers. We provide evidence using a unique dataset on individual retirement decisions in Swiss pension funds, allowing us to perfectly control for pension scheme details. Our findings suggest that affordability is a key determinant in the retirement decisions. The higher the accumulated pension capital, the earlier men, and to a smaller extent women, tend to leave the workforce. The fact that early retirement has become much more prevalent in the last 15 years is a further indicator of the importance of a wealth effect, as the maturing of the Swiss mandatory funded pension system over that period has led to an increase in the effective replacement rates for middle and high income earners. Part two covers the theoretical side of social security. Theories analyzing optimal social security benefits provide important qualitative results, by mainly using one general type of an economy. Economies are however very diverse concerning numerous aspects, one of the most important being the wealth level. This can lead to significant quantitative benefit differences that imply differences in replacement rates and levels of labor supply. We focus on several aspects related to this fact. In a within cohort social security model, we introduce disability insurance with an imperfect screening mechanism. We then vary the wealth level of the model economy and analyze how the optimal social security benefit structure or equivalently, the optimal replacement rates, changes depending on the wealth level of the economy, and if the introduction of disability insurance into a social security system is preferable for all economies. Second, the screening mechanism of disability insurance and the threshold level at which people are defined as disabled can differ. For economies with different wealth levels, we determine for different thresholds the screening level that maximizes social welfare. Finally, part three turns to the income of governments, by adding an element to the controversy on tax competition versus tax harmonization.2 Inter-jurisdictional tax competition can generate at least two potential benefits or costs: On a public level, tax competition may result in a lower or higher efficiency in the production of public services. But there is also a more private benefit in the form of an option for individuals to move to a community with a lower tax rate in the future. To explore the value citizens attach to tax competition we analyze a unique popular vote for a complete tax harmonization between communities in the third largest Swiss canton, Vaud. Although a majority of voters would have seemingly benefited from replacing the current tax rate by a revenue-neutral average tax rate, the proposal was rejected by a large margin. Our estimates suggest that the estimated combined perceived benefit from tax competition is in the range of 10%.

Effect of carbohydrate overfeeding on whole body and adipose tissue metabolism in humans.

OBJECTIVE: To evaluate the effect of a 4-day carbohydrate overfeeding on whole body net de novo lipogenesis and on markers of de novo lipogenesis in subcutaneous adipose tissue of healthy lean humans. RESEARCH METHODS AND PROCEDURES: Nine healthy lean volunteers (five men and four women) were studied after 4 days of either isocaloric feeding or carbohydrate overfeeding. On each occasion, they underwent a metabolic study during which their energy expenditure and net substrate oxidation rates (indirect calorimetry), and the fractional activity of the pentose-phosphate pathway in subcutaneous adipose tissue (subcutaneous microdialysis with 1,6(13)C2,6,6(2)H2 glucose) were assessed before and after administration of glucose. Adipose tissue biopsies were obtained at the end of the experiments to monitor mRNAs of key lipogenic enzymes. RESULTS: Carbohydrate overfeeding increased basal and postglucose energy expenditure and net carbohydrate oxidation. Whole body net de novo lipogenesis after glucose loading was markedly increased at the expense of glycogen synthesis. Carbohydrate overfeeding also increased mRNA levels for the key lipogenic enzymes sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase. The fractional activity of adipose tissue pentose-phosphate pathway was 17% to 22% and was not altered by carbohydrate overfeeding. DISCUSSION: Carbohydrate overfeeding markedly increased net de novo lipogenesis at the expense of glycogen synthesis. An increase in mRNAs coding for key lipogenic enzymes suggests that de novo lipogenesis occurred, at least in part, in adipose tissue. The pentose-phosphate pathway is active in adipose tissue of healthy humans, consistent with an active role of this tissue in de novo lipogenesis.

Disease identification based on ambulatory drugs dispensation and in-hospital ICD-10 diagnoses: a comparison.

BACKGROUND: Pharmacy-based case mix measures are an alternative source of information to the relatively scarce outpatient diagnoses data. But most published tools use national drug nomenclatures and offer no head-to-head comparisons between drugs-related and diagnoses-based categories. The objective of the study was to test the accuracy of drugs-based morbidity groups derived from the World Health Organization Anatomical Therapeutic Chemical Classification of drugs by checking them against diagnoses-based groups. METHODS: We compared drugs-based categories with their diagnoses-based analogues using anonymous data on 108,915 individuals insured with one of four companies. They were followed throughout 2005 and 2006 and hospitalized at least once during this period. The agreement between the two approaches was measured by weighted kappa coefficients. The reproducibility of the drugs-based morbidity measure over the 2 years was assessed for all enrollees. RESULTS: Eighty percent used a drug associated with at least one of the 60 morbidity categories derived from drugs dispensation. After accounting for inpatient under-coding, fifteen conditions agreed sufficiently with their diagnoses-based counterparts to be considered alternative strategies to diagnoses. In addition, they exhibited good reproducibility and allowed prevalence estimates in accordance with national estimates. For 22 conditions, drugs-based information identified accurately a subset of the population defined by diagnoses. CONCLUSIONS: Most categories provide insurers with health status information that could be exploited for healthcare expenditure prediction or ambulatory cost control, especially when ambulatory diagnoses are not available. However, due to insufficient concordance with their diagnoses-based analogues, their use for morbidity indicators is limited.

Rôle du transporteur de glucose GLUT2 dans les mécanismes centraux de glucodétection impliqués dans le contrôle de la sécrétion du glucagon et de la prise alimentaire

Résumé Rôle du transporteur de glucose GLUT2 dans les mécanismes centraux de glucodétection impliqués dans le contrôle de la sécrétion du glucagon et de la prise alimentaire. Les mécanismes centraux de glucodétection jouent un rôle majeur dans le contrôle de l'homéostasie glucidique. Ces senseurs régulent principalement la sécrétion des hormones contre-régulatrices, la prise alimentaire et la dépense énergétique. Cependant, la nature cellulaire et le fonctionnement moléculaire de ces mécanismes ne sont encore que partiellement élucidés. Dans cette étude, nous avons tout d'abord mis en évidence une suppression de la stimulation de la sécrétion du glucagon et de la prise alimentaire en réponse à une injection intracérébroventriculaire (i.c.v.) de 2-déoxy-D-glucose (2-DG) chez les souris de fond génétique mixte et déficientes pour le gène glut2 (souris RIPG1xglut2-/-). De plus, chez ces souris, l'injection de 2-DG n'augmente pas l'activation neuronale dans l'hypothalamus et le complexe vagal dorsal. Nous avons ensuite montré que la ré-expression de GLUT2 dans les neurones des souris RIPG1xg1ut2-/- ne restaure pas la sécrétion du glucagon et la prise alimentaire en réponse à une injection i.c.v. de 2-DG. En revanche, l'injection de 2-DG réalisée chez les souris RIPG1xg1ut2-/- ré-exprimant le GLUT2 dans leurs astrocytes, stimule la sécrétion du glucagon et l'activation neuronale dans le complexe vagal dorsal mais n'augmente pas la prise alimentaire ni l'activation neuronale dans l'hypothalamus. L'ensemble de ces résultats démontre l'existence de différents mécanismes centraux de glucodétection dépendants de GLUT2. Les mécanismes régulant la sécrétion du glucagon sont dépendants de GLUT2 astrocytaire et pourraient être localisés dans le complexe vagal dorsal. L'implication des astrocytes dans ces mécanismes suggère un couplage fonctionnel entre les astrocytes et les neurones adjacents « sensibles au glucose ». Lors de cette étude, nous avons remarqué chez les souris RIPG1xg1ut2-/- de fond génétique pur C57B1/6, que seul le déclenchement de la prise alimentaire en réponse à l'injection i.p. ou i.c.v. de 2-DG est aboli. Ces données mettent en évidence que suivant le fond génétique de la souris, les mécanismes centraux de glucodétection impliqués dans la régulation de la sécrétion peuvent être indépendants de GLUT2. Summary. Role of transporter GLUT2 in central glucose sensing involved in the control of glucagon secretion and food intake. Central glucose sensors play an important role in the control of glucose homeostasis. These sensors regulate general physiological functions, including food intake, energy expenditure and hormones secretion. So far the cellular and molecular basis of central glucose detection are poorly understood. Hypoglycemia, or cellular glucoprivation by intraperitoneal injection of 2-deoxy¬glucose (2-DG) injection, elicit multiple glucoregulatory responses, in particular glucagon secretion and stimulation of feeding. We previously demonstrated that the normal glucagon response to insulin-induced hypoglycemia was suppressed in mice lacking GLUT2. This indicated the existence of extra-pancreatic, GLUT2-dependent, glucose sensors controllling glucagon secretion. Here, we have demonstrated that the normal glucagon and food intake responses to central glucoprivation, by intracerebroventricular (i.c.v.) injections of 2-DG, were suppressed in mice lacking GLUT2 (RIPG1xglut2-/- mice) indicating that GLUT2 plays a role in central glucose sensing units controlling secretion of glucagon and food intake. Whereas it is etablished that glucose responsive neurons change their firing rate in response to variations of glucose concentrations, the exact mechanism of glucose detection is not established. In particular, it has been suggested that astrocytic cells may be the primary site of glucose detection and that a signal is subsequently transmitted to neurons. To evaluate the respective role of glial and neuronal expression of GLUT2 in central glucodetection, we studied hypoglycemic and glucoprivic responses following cellular glucoprivation in RIPG1xglut2-/- mice reexpressing the transgenic GLUT2 specifially in their astrocytes (pGFAPG2xRIPG1xglut2-/- mice) or their neurons (pSynG2xRIPG1xglut2-/- mice). The increase of food intake after i.p. injection of 2-DG in control mice was not observed in the pGFAPG2xRIPG1xglut2-/- mice. Whereas a strong increase of glucagon secretion was observed in control and pGFAPG2xRIPG1xglut2-/- mice, not glucagonemic response was induced in pSynG2xRIPG1xglut2-/- mice. Our results show that GLUT2 reexpression in glial cells but not in neurons restored glucagon secretion and thus present a strong evidence that glucose detection and the control of glucagon secretion require a coupling between glial cells and neurons. Furthermore, these results show the existence of differents glucose sensors in CNS. Résumé tout public. Rôle du transporteur de glucose GLUT2 dans les mécanismes centraux de glucodétection impliqués dans le contrôle de la sécrétion du glucagon et de la prise alimentaire. Chez les mammifères, en dépit des grandes variations dans l'apport et l'utilisation du glucose, la glycémie est maintenue à une valeur relativement constante d'environ 1 g/l. Cette régulation est principalement sous le contrôle de deux hormones produites par le pancréas l'insuline et le glucagon. A la suite d'un repas, la détection de l'élévation de la glycémie par le pancréas permet la libération pancréatique de l'insuline dans le sang. Cette hormone va alors permettre le stockage dans le foie du glucose sanguin en excès et diminuer ainsi la glycémie. Sans insuline, le glucose s'accumule dans le sang. On parle alors d'hyperglycémie chronique. Cette situation est caractéristique du diabète et augmente les risques de maladies cardiovasculaires. A l'inverse, lors d'un jeûne, la détection de la diminution de la glycémie par le cerveau permet le déclenchement de la prise alimentaire et stimule la sécrétion de glucagon par le pancréas. Le glucagon va alors permettre la libération dans le sang du glucose stocké par le foie. Les effets du glucagon et de la prise de nourriture augmentent ainsi les concentrations sanguines de glucose pour empêcher une diminution trop importante de la glycémie. Une hypoglycémie sévère peut entraîner un mauvais fonctionnement du cerveau allant jusqu'à des lésions cérébrales. Contrairement aux mécanismes pancréatiques de détection du glucose, les mécanismes de glucodétection du cerveau ne sont encore que partiellement élucidés. Dans le laboratoire, nous avons observé, chez les souris transgéniques n'exprimant plus le transporteur de glucose GLUT2, une suppression de la stimulation de la sécrétion du glucagon et du déclenchement de la prise alimentaire en réponse à une hypoglycémie, induite uniquement dans le cerveau. Dans le cerveau, le GLUT2 est principalement exprimé par les astrocytes, cellules gliales connues pour soutenir, nourrir et protéger les neurones. Nous avons alors ré-exprimé spécifiquement le GLUT2 dans les astrocytes des souris transgéniques et nous avons observé que seule la stimulation de la sécrétion du glucagon en réponse à l'hypoglycémie est restaurée. Ces résultats mettent en évidence que la sécrétion du glucagon et la prise alimentaire sont contrôlées par différents mécanismes centraux de glucodétection dépendants de GLUT2.

Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism.

Ghrelin is an endogenous regulator of energy homeostasis synthesized by the stomach to stimulate appetite and positive energy balance. Similarly, the endocannabinoid system is part of our internal machinery controlling food intake and energy expenditure. Both peripheral and central mechanisms regulate CB1-mediated control of food intake and a functional relationship between hypothalamic ghrelin and cannabinoid CB1 receptor has been proposed. First of all, we investigated brain ghrelin actions on food intake in rats with different metabolic status (negative or equilibrate energy balance). Secondly, we tested a sub-anxiogenic ultra-low dose of the CB1 antagonist SR141716A (Rimonabant) and the peripheral-acting CB1 antagonist LH-21 on ghrelin orexigenic actions. We found that: 1) central administration of ghrelin promotes food intake in free feeding animals but not in 24 h food-deprived or chronically food-restricted animals; 2) an ultra-low dose of SR141716A (a subthreshold dose 75 folds lower than the EC50 for induction of anxiety) completely counteracts the orexigenic actions of central ghrelin in free feeding animals; 3) the peripheral-restricted CB1 antagonist LH-21 blocks ghrelin-induced hyperphagia in free feeding animals. Our study highlights the importance of the animaĺs metabolic status for the effectiveness of ghrelin in promoting feeding, and suggests that the peripheral endocannabinoid system may interact with ghrelińs signal in the control of food intake under equilibrate energy balance conditions.

Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study.

BACKGROUND Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation. METHODS The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo. RESULTS The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events. CONCLUSIONS The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Motor overactivity and loss of motor circadian rhythm in fatal familial insomnia: an actigraphic study.

The 24-hour rest-activity pattern and the amount of motor activity was studied in a patient with fatal familial insomnia (FFI) by means of wrist actigraphy. During the study, the patient underwent indirect calorimetry. The 52-day recording showed severe disruption of the 24-hour rest-activity pattern with increased motor activity up to 80%. The 24-hour energy expenditure, assayed in a respiration chamber, was strikingly elevated by 60%. Chronic motor overactivity and loss of circadian rest-activity rhythm may play a role in the progressive metabolic exhaustion leading to death in FFI patients.

Lack of thermogenic response to glucose/insulin infusion in diabetic obese subjects.

The change in energy expenditure consecutive to the infusion of glucose/insulin was examined in 17 non-obese (ten young, seven middle-aged) and 27 diabetic and non-diabetic obese subjects by employing the euglycemic insulin clamp technique in conjunction with continuous indirect calorimetry. The obese subjects were divided into four groups according to their response to a 100-g oral glucose test: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with increased insulin response; group D, diabetes with reduced insulin response. The glucose/insulin infusion provoked an increase in energy expenditure in both young and middle-aged controls (+8.2 +/- 1.3 percent and +5.9 +/- 0.5 percent over the preinfusion baseline respectively), but a lower increase in the non-diabetic obese groups A and B (+4.0 +/- 0.7 percent and +2.0 +/- 1.0 percent over the preinfusion baseline respectively, P less than 0.05 and P less than 0.01 vs young controls). However, in the diabetic obese groups C and D, energy expenditure failed to increase in response to the glucose/insulin infusion (mean change: +0.1 +/- 1.0 percent and -2.0 +/- 1.9 percent (P less than 0.01, vs middle-aged) over the preinfusion baseline respectively). When the glucose-induced thermogenesis (GIT) was related to the glucose uptake--taking into account the hepatic glucose production--the GIT was found to be similarly reduced in the diabetics groups (C and D). The net change in the rate of energy expenditure was found to be significantly correlated with the rate of glucose uptake (r = +0.647, n = 44, P less than 0.001) when all the individuals were pooled. In conclusion, this study shows that the low glucose-induced thermogenesis in obese diabetics during glucose insulin infusion is mainly related to a reduced rate of glucose uptake; in addition, inhibition of gluconeogenesis by the glucose/insulin infusion may also contribute to decrease the thermogenic response.

The forgotten face of regular physical exercise: a 'natural' anti-atherogenic activity.

Humans are not programmed to be inactive. The combination of both accelerated sedentary lifestyle and constant food availability disturbs ancient metabolic processes leading to excessive storage of energy in tissue, dyslipidaemia and insulin resistance. As a consequence, the prevalence of Type 2 diabetes, obesity and the metabolic syndrome has increased significantly over the last 30 years. A low level of physical activity and decreased daily energy expenditure contribute to the increased risk of cardiovascular morbidity and mortality following atherosclerotic vascular damage. Physical inactivity leads to the accumulation of visceral fat and consequently the activation of the oxidative stress/inflammation cascade, which promotes the development of atherosclerosis. Considering physical activity as a 'natural' programmed state, it is assumed that it possesses atheroprotective properties. Exercise prevents plaque development and induces the regression of coronary stenosis. Furthermore, experimental studies have revealed that exercise prevents the conversion of plaques into a vulnerable phenotype, thus preventing the appearance of fatal lesions. Exercise promotes atheroprotection possibly by reducing or preventing oxidative stress and inflammation through at least two distinct pathways. Exercise, through laminar shear stress activation, down-regulates endothelial AT1R (angiotensin II type 1 receptor) expression, leading to decreases in NADPH oxidase activity and superoxide anion production, which in turn decreases ROS (reactive oxygen species) generation, and preserves endothelial NO bioavailability and its protective anti-atherogenic effects. Contracting skeletal muscle now emerges as a new organ that releases anti-inflammatory cytokines, such as IL-6 (interleukin-6). IL-6 inhibits TNF-α (tumour necrosis factor-α) production in adipose tissue and macrophages. The down-regulation of TNF-α induced by skeletal-muscle-derived IL-6 may also participate in mediating the atheroprotective effect of physical activity.

Leucine supplementation protects from insulin resistance by regulating adiposity levels.

BACKGROUND Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. METHODOLOGY/PRINCIPAL FINDINGS Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. CONCLUSIONS/SIGNIFICANCE These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.