Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: A key to lean phenotype

AbstractWe are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non-shivering thermogenesis occurring both in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT). Because contribution of WAT to resting metabolic rate is relatively small, the possibility to reduce adiposity by enhancing energy expenditure in classical white adipocytes is largely neglected. However, several pieces of evidence support a notion that induction of energy expenditure based on oxidation of fatty acids (FA) in WAT may be beneficial for health, namely: (i) studies in both humans and rodents document negative association between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats as well as cold-acclimation of UCP1-ablated mice results in obesity resistance associated with increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed a high-fat diet; this was associated with strong hypolipidemic and insulin-sensitizing effects, as well as prevention of inflammation, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and FA oxidation, specifically in epididymal WAT. Importantly, these changes occurred without induction of UCP1 and suggested the involvement of: (i) futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglycerols and re-esterification of FA, in association with the induction of mitochondrial OXPHOS capacity, β-oxidation, and energy expenditure; (ii) endogenous lipid mediators (namely endocannabinoids, eicosanoids, prostanoids, resolvins, and protectins) and their cognate receptors; and (iii) AMP-activated protein kinase in WAT. Quantitatively, the strong induction of FA oxidation in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT. The induction of UCP1-independent FA oxidation and energy expenditure in WAT in response to the above physiological stimuli could underlie the amelioration of obesity and low-grade WAT inflammation, and it could reduce the release of FA from adipose tissue and counteract harmful consequences of lipid accumulation in other tissues. In this respect, new combination treatments may be designed using naturally occurring micronutrients (e.g. omega 3), reduced calorie intake or pharmaceuticals, exerting synergism in the induction of the mitochondrial OXPHOS capacity and stimulation of lipid catabolism in white adipocytes, and improving metabolic flexibility of WAT. The role of mutual interactions between adipocytes and immune cells contained in WAT in tissue metabolism should be better characterised. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease

Dicarbonyl stress and beta-cell dysfunction

Methylglyoxal may be involved in the early stages of decline in glucose tolerance and decline in pancreatic beta-cell function leading to type 2 diabetes. Methylglyoxal and methylglyoxal-modified proteins increase during short-term increases in glucose concentration, infusion of exogenous methylglyoxal in rats and mice impaired glucose tolerance and glyoxalase 1 (Glo1) prevented beta-cell toxicity. We investigated the role of methylglyoxal and protein glycation on beta-cell function and the development of diabetes, with focus on the interactions of cells with the extracellular matrix. Impairments in adhesion of MIN6 insulinoma cells to methylglyoxal-glycated collagen IV were assessed in vitro using atomic force microscopy force spectroscopy and methylglyoxal glycation adducts within the pancreas visualised by immunostaining. Minimal glycation of collagen IV at integrin binding sites impaired binding of MIN6 cells in vitro and resulted in a 91% decrease in the energy necessary to detach the cells from collagen. Evidence from high fat diet fed mice showed that the methylglyoxal concentration of the pancreas was increased in the insulin resistant, pre-diabetic state with methylglyoxal-derived glycation adducts within the pancreas predominantly localised to the extracellular matrix in vivo. We conclude that glycation of extracellular matrix collagen IV likely impairs adhesion of beta-cells to the extracellular matrix in pre-diabetes in vivo and may thereby contribute to beta-cell glucotoxicity and dysfunction with progression to type 2 diabetes mellitus

BIOCLAIMS standard diet (BIOsd): a reference diet for nutritional physiology

Experimental replication is fundamental for practicing science. To reduce variability, it is essential to control sources of variation as much as possible. Diet is an important factor that can influence many processes and functional outcomes in studies performed with rodent models. This is especially true for, but not limited to, nutritional studies. To compare functional effects of different nutrients, it is important to use standardized, semi-purified diets. Here, we propose and describe a standard reference diet, the BIOCLAIMS standard diet. The diet is AIN-93 based, but further defined with dietary and experimental requirements taken into account that allow for experiments with bioactive food components and natural (non-expensive) labeling. This diet will be implemented by two European research consortia, Mitofood and BIOCLAIMS, to ensure inter-laboratory comparability

Unmasking Differential Effects of Rosiglitazone and Pioglitazone in the Combination Treatment with n-3 Fatty Acids in Mice Fed a High-Fat Diet

Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy

A meta-analysis of global fungal distribution reveals climate-driven patterns

The evolutionary and environmental factors that shape fungal biogeography are incompletely understood. Here, we assemble a large dataset consisting of previously generated mycobiome data linked to specific geographical locations across the world. We use this dataset to describe the distribution of fungal taxa and to look for correlations with different environmental factors such as climate, soil and vegetation variables. Our meta-study identifies climate as an important driver of different aspects of fungal biogeography, including the global distribution of common fungi as well as the composition and diversity of fungal communities. In our analysis, fungal diversity is concentrated at high latitudes, in contrast with the opposite pattern previously shown for plants and other organisms. Mycorrhizal fungi appear to have narrower climatic tolerances than pathogenic fungi. We speculate that climate change could affect ecosystem functioning because of the narrow climatic tolerances of key fungal taxa

Teaching child and adolescent psychiatry to undergraduate medical students - A survey in German-speaking countries

Objective To conduct a survey about teaching child and adolescent psychiatry to undergraduate medical students in German-speaking countries. Methods A questionnaire was sent to the 33 academic departments of child and adolescent psychiatry in Germany, Austria, and the German-speaking part of Switzerland. Results All departments responded. For teaching knowledge, the methods most commonly reported were lectures and case presentations. The most important skills to be taught were thought to be how to assess psychopathology in children and how to assess families. For elective courses, the departments reported using a wide range of teaching methods, many with active involvement of the students. An average of 34 hours per semester is currently allocated by the departments for teaching child and adolescent psychiatry to medical students. Required courses are often taught in cooperation with adult psychiatry and pediatrics. Achievement of educational objectives is usually assessed with written exams or multiple-choice tests. Only a minority of the departments test the achievement of skills. Conclusions Two ways of improving education in child and adolescent psychiatry are the introduction of elective courses for students interested in the field and participation of child and adolescent psychiatrists in required courses and in longitudinal courses so as to reach all students. Cooperation within and across medical schools can enable departments of child and adolescent psychiatry, despite limited resources, to become more visible and this specialty to become more attractive to medical students. Compared to the findings in earlier surveys, this survey indicates a trend towards increased involvement of academic departments of child and adolescent psychiatry in training medical students

Metastatic breast carcinoma of the coracoid process: two case reports

<p>Abstract</p> <p>Background</p> <p>The coracoid process of the scapula is a rare site of involvement for metastatic disease or for primary tumors. We are unaware of any reports in the literature of pathologic coracoid process fractures and only one report of metastatic disease to the coracoid.</p> <p>Methods and Results</p> <p>In this case report, we present two cases with metastatic breast carcinoma of the coracoid process, one of which presented with a pathologic fracture of the coracoid.</p> <p>Conclusions</p> <p>An orthopaedic surgeon must be aware of the potential for metastatic disease to the coracoid as they may be the first medical provider to encounter evidence of malignant disease.</p

The deuteron: structure and form factors

A brief review of the history of the discovery of the deuteron in provided. The current status of both experiment and theory for the elastic electron scattering is then presented.Comment: 80 pages, 33 figures, submited to Advances in Nuclear Physic