Diet and gene interactions influence the skeletal response to polyunsaturated fatty acids.

Diets rich in omega-3s have been thought to prevent both obesity and osteoporosis. However, conflicting findings are reported, probably as a result of gene by nutritional interactions. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor that improves insulin sensitivity but causes weight gain and bone loss. Fish oil is a natural agonist for PPARγ and thus may exert its actions through the PPARγ pathway. We examined the role of PPARγ in body composition changes induced by a fish or safflower oil diet using two strains of C57BL/6J (B6); i.e. B6.C3H-6T (6T) congenic mice created by backcrossing a small locus on Chr 6 from C3H carrying 'gain of function' polymorphisms in the Pparγ gene onto a B6 background, and C57BL/6J mice. After 9months of feeding both diets to female mice, body weight, percent fat and leptin levels were less in mice fed the fish oil vs those fed safflower oil, independent of genotype. At the skeletal level, fish oil preserved vertebral bone mineral density (BMD) and microstructure in B6 but not in 6T mice. Moreover, fish oil consumption was associated with an increase in bone marrow adiposity and a decrease in BMD, cortical thickness, ultimate force and plastic energy in femur of the 6T but not the B6 mice. These effects paralleled an increase in adipogenic inflammatory and resorption markers in 6T but not B6. Thus, compared to safflower oil, fish oil (high ratio omega-3/-6) prevents weight gain, bone loss, and changes in trabecular microarchitecture in the spine with age. These beneficial effects are absent in mice with polymorphisms in the Pparγ gene (6T), supporting the tenet that the actions of n-3 fatty acids on bone microstructure are likely to be genotype dependent. Thus caution must be used in interpreting dietary intervention trials with skeletal endpoints in mice and in humans

Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

Nicotinic acetylcholine receptors (nAChRs) are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine or other biologic compounds including nicotine. Their roles in synaptic transmission in the central and peripheral nervous system as well as in the neuromuscular junction have been extensively studied. Recent implications of nAChRs in intracellular signaling and their detection in peripheral nonneural cells (including epithelial cells and immune cells) have renewed the interest for this class of ionotropic receptors. In the present review, we focus our attention on the potential use of nicotinic cholinergic signaling in the treatment of metabolic diseases (such as obesity and diabetes) in browsing functions of nAChRs in adipose tissue and pancreatic islet biology. In fact, different nAChR subunits can be detected in these metabolic tissues, as well as in immune cells interacting with them. Various rodent models of obesity and diabetes benefit from stimulation of the nicotinic cholinergic pathway, whereas mice deficient for some nAChRs, in particular the α7 nAChR subunit, harbor a worsened metabolic phenotype. In contrast to potential therapeutic applications in metabolic diseases, an overstimulation of this signaling pathway during the early stage of development (typically through nicotine exposure during fetal life) presents deleterious consequences on ontogeny and functionality of adipose tissue and the endocrine pancreas which persist throughout life

Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner.

Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain-dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms

"Leistung" in der Marktgesellschaft: eine empirische Zwischenbilanz

"Der Vortrag soll eine erste systematische Zwischenbilanz der Ergebnisse des DFGProjektes 'Leistung in der Marktgesellschaft - Erosion eines Deutungsmusters?' geben, das seit Juli 2002 am Institut für Sozialforschung in Frankfurt am Main durchgeführt wird. Im Zentrum des Projektes steht die Frage, welche normative Relevanz das Leistungsprinzip als Rechtfertigungskriterium sozialer Statusungleichheiten heute hat. Dazu wurden bei ausgewählten Sozialgruppen gegenwärtig relevante Deutungs- und Rechtfertigungsmuster sozialer Statuszuschreibung mittels rekonstruktiv-hermeneutischer Verfahren erhoben und daraufhin untersucht, welche Rolle Leistungskategorienin ihnen zukommt. Dabei können wir feststellen, das 'Leistung' sich mit sehr unterschiedlichen Wertbeständen und Deutungsressourcen verbinden kann, so dass im Ergebnis auch die jeweiligen Leistungsverständnisse deutlich differieren. Diese stehen jedoch nicht konfliktfrei nebeneinander (etwa im Sinne eines Wertpluralismus). Sie sind sozial ungleich verteilt und konkurrieren um die legitimen, normativen Grundlagen der gesellschaftlichen Statusordnung. Sie spiegeln (latente wie offene) 'Kämpfe um Anerkennung', in denen die unterschiedlichen Sozialgruppen darum ringen, was als 'Leistung' gelten und damit zu einer Quelle sozialer Wertschätzung werden soll. Außerdem stehen diese Leistungsverständnisse in mehr oder weniger starker Spannung zudem normativen Kernbestand des Leistungsprinzips, der in das Selbstverständnis der bürgerlichen Gesellschaft als eine fundamentale Bestandsnorm eingelassen ist. Die Relevanz des Leistungsprinzips erweist sich also gerade auch darin, ob es überhaupt noch einen übergreifenden, normativen Deutungshorizont darstellt, der den sozialdifferenzierten Leistungsverständnissen als eine gemeinsame, integrative Referenz dienen kann." (Autorenreferat

NFE2-Related transcription factor 2 coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland

Background: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. Methods: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. Results: The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. Conclusions: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.Fil: Ziros, Panos G. Lausanne University; SuizaFil: Habeos, Ioannis. Patras University; GreciaFil: Chartoumpekis, Dionysios V. University of Pittsburgh; Estados UnidosFil: Ntalampyra, Eleni. Universite de Lausanne; SuizaFil: Somm, Emmanuel. Universite de Lausanne; SuizaFil: Renaud, Cédric O.. Universite de Lausanne; SuizaFil: Bongiovanni, Massimo. Institute Of Pathology Locarno; SuizaFil: Trougakos, Ioannis P. Universidad Nacional y Kapodistríaca de Atenas; GreciaFil: Yamamoto, Masayuki. University Of Tohoku; JapónFil: Kensler, Thomas W.. University of Pittsburgh at Johnstown; Estados UnidosFil: Santisteban, Pilar. Universidad Autónoma de Madrid; EspañaFil: Carrasco, Nancy. University of Yale. School of Medicine; Estados UnidosFil: Ris Stalpers, Carrie. Academic Medical Center; Países BajosFil: Amendola, Elena. Universidad de Nápoles; ItaliaFil: Liao, Xiao-Hui. University of Chicago; Estados UnidosFil: Rossich, Luciano Esteban. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Thomasz, Lisa. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juvenal, Guillermo Juan. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Refetoff, Samuel. University of Chicago; Estados UnidosFil: Sykiotis, Gerasimos P.. Universite de Lausanne; Suiz

Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents

Aims/hypothesis: The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents. Methods: We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents. Results: We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn −/− animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn −/− animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake. Conclusions/interpretation: The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistanc

Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology 149

ABSTRACT Despite medical advice, 20% to 30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3mg/kg in Sprague-Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 days of life (PND7) which corroborates with a decrease in gene expression of specific transcription factors such as Pdx-1, Pax-6, Nkx6.1 and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue (eWAT) weight at weaning (PND21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as C/EBP-α, PPAR-γ and SREBP-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high fat diet, cold intolerance, reduced physical activity, glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development

An automated optimization pipeline for clinical-grade computer-assisted planning of high tibial osteotomies under consideration of weight-bearing

3D preoperative planning for high tibial osteotomies (HTO) has increasingly replaced 2D planning but is complex, time-consuming and therefore expensive. Several interdependent clinical objectives and constraints have to be considered, which often requires multiple rounds of revisions between surgeons and biomedical engineers. We therefore developed an automated preoperative planning pipeline, which takes imaging data as an input to generate a ready-to-use, patient-specific planning solution. Deep-learning based segmentation and landmark localization was used to enable the fully automated 3D lower limb deformity assessment. A 2D-3D registration algorithm allowed the transformation of the 3D bone models into the weight-bearing state. Finally, an optimization framework was implemented to generate ready-to use preoperative plannings in a fully automated fashion, using a genetic algorithm to solve the multi-objective optimization (MOO) problem based on several clinical requirements and constraints. The entire pipeline was evaluated on a large clinical dataset of 53 patient cases who previously underwent a medial opening-wedge HTO. The pipeline was used to automatically generate preoperative solutions for these patients. Five experts blindly compared the automatically generated solutions to the previously generated manual plannings. The overall mean rating for the algorithm-generated solutions was better than for the manual solutions. In 90% of all comparisons, they were considered to be equally good or better than the manual solution. The combined use of deep learning approaches, registration methods and MOO can reliably produce ready-to-use preoperative solutions that significantly reduce human workload and related health costs

Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3

Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3.Russell AP, Schrauwen P, Somm E, Gastaldi G, Hesselink MK, Schaart G, Kornips E, Lo SK, Bufano D, Giacobino JP, Muzzin P, Ceccon M, Angelini C, Vergani L.Department of Medical Biochemistry, University of Geneva Medical Center, 1206 Geneva, Switzerland. [email protected], multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) beta-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA beta-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA beta-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid beta-oxidation.<br/

Perinatal Exposure to Bisphenol A Alters Early Adipogenesis in the Rat

BACKGROUND: The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has been poorly investigated. OBJECTIVES: The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. METHODS: Pregnant Sprague-Dawley rats had access to drinking water containing 1 mg/L BPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. RESULTS: Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-alpha (CAAT enhancer binding protein alpha), PPAR-gamma (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex- and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. CONCLUSIONS: Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors