Misconceptions about fructose-containing sugars and their role in the obesity epidemic.

A causal role of fructose intake in the aetiology of the global obesity epidemic has been proposed in recent years. This proposition, however, rests on controversial interpretations of two distinct lines of research. On one hand, in mechanistic intervention studies, detrimental metabolic effects have been observed after excessive isolated fructose intakes in animals and human subjects. On the other hand, food disappearance data indicate that fructose consumption from added sugars has increased over the past decades and paralleled the increase in obesity. Both lines of research are presently insufficient to demonstrate a causal role of fructose in metabolic diseases, however. Most mechanistic intervention studies were performed on subjects fed large amounts of pure fructose, while fructose is ordinarily ingested together with glucose. The use of food disappearance data does not accurately reflect food consumption, and hence cannot be used as evidence of a causal link between fructose intake and obesity. Based on a thorough review of the literature, we demonstrate that fructose, as commonly consumed in mixed carbohydrate sources, does not exert specific metabolic effects that can account for an increase in body weight. Consequently, public health recommendations and policies aiming at reducing fructose consumption only, without additional diet and lifestyle targets, would be disputable and impractical. Although the available evidence indicates that the consumption of sugar-sweetened beverages is associated with body-weight gain, and it may be that fructose is among the main constituents of these beverages, energy overconsumption is much more important to consider in terms of the obesity epidemic.

Prevalence of obesity and abdominal obesity in the Lausanne population.

BACKGROUND: Obesity can be defined using body mass index (BMI) or waist (abdominal obesity). Little information exists regarding its prevalence and determinants in Switzerland. Hence, we assessed the levels of obesity as defined by BMI or waist circumference in a Swiss population-based sample. METHODS: Cross-sectional, population-based non-stratified random sample of 3,249 women and 2,937 men aged 35-75 years living in Lausanne, Switzerland. Overall participation rate was 41%. RESULTS: In men, the prevalences of overweight (BMI > or =25 kg/m2) and obesity (BMI > or =30 kg/m2) were 45.5% and 16.9%, respectively, higher than in women (28.3% and 14.3%, respectively). The prevalence of abdominal obesity (waist > or =102 in men and > or =88 cm in women) was higher in women than in men (30.6% vs. 23.9%). Obesity and abdominal obesity increased with age and decreased with higher educational level in both genders. In women, the prevalence of obesity was lower among former and current smokers, whereas in men the prevalence of obesity was higher in former smokers but did not differ between current and never smokers. Multivariate analysis showed age to be positively related, and education and physical activity to be negatively related with obesity and abdominal obesity in both genders, whereas differential effects of smoking were found between genders. CONCLUSION: The prevalence of abdominal obesity is higher than BMI-derived obesity in the Swiss population. Women presented with more abdominal obesity than men. The association between smoking and obesity levels appears to differ between genders.

Recent human-induced trophic change in the large and deep perialpine Lake Lucerne (Switzerland) compared to historical geochemical variations

This study investigates the sedimentological and geochemical changes that occurred during the last 2200 years in the meromictic Lake Lucerne (Switzerland), one of the largest freshwater lakes of Central Europe. The stable isotope composition (delta C-13 and delta O-18 values) of bulk carbonates is compared to changes in grain-size distribution (clay and silt fraction), natural trace element input (titanium and thorium concentrations), and organic material abundance (C-org, nitrogen and phosphorus) and composition (C/N ratios and hydrogen and oxygen indexes). A drop in carbonate accumulation and in the delta O-18 values of sediments between ca. AD 500 and 700 followed a large and consistent rise in chemical weathering, marked by increases in the silicate-clay fraction and in crustal element concentrations. During the following millennium, there was a long-term decreasing trend in the lithogenic trace element input and in the phosphorus loading, suggesting decreasing terrigeneous input from runoff water. The major sedimentological change over the studied period occurred after ca. AD 1800 with a significant increase in the erosion-driven silt-fraction and in the sedimentation rate. During the last century, human-induced increase in nutrient input to the lake highly enhanced the accumulation of organic matter in sediment. Changes in nutrients and oxygen conditions in the hypolimnion of Lake Lucerne during the eutrophication period (i.e., the last 40 years) highly modified the geochemical fluxes compared to the relatively stable oligotrophic conditions that prevailed during the previous 2000 years. Before the 19th century, climate driven meromixis had a limited impact on the organic matter flux to the sediments, but the accumulation of carbonate considerably decreased during periods of lower mechanical erosion rates and high chemical weathering rates. (C) 2012 Elsevier B.V. All rights reserved.

Mating order-dependent female mate choice in the polygynandrous common lizard Lacerta vivipara.

Recent studies indicate that directional female mate choice and order-dependent female mate choice importantly contribute to non-random mating patterns. In species where females prefer larger sized males, disentangling different hypotheses leading to non-random mating patterns is especially difficult, given that male size usually correlates with behaviours that may lead to non-random mating (e.g. size-dependent emergence from hibernation, male fighting ability). Here we investigate female mate choice and order-dependent female mate choice in the polygynandrous common lizard (Lacerta vivipara). By sequentially presenting males in random order to females, we exclude non-random mating patterns potentially arising due to intra-sexual selection (e.g. male-male competition), trait-dependent encounter probabilities, trait-dependent conspicuousness, or trait-dependent emergence from hibernation. To test for order-dependent female mate choice we investigate whether the previous mating history affects female choice. We show that body size and body condition of the male with which a female mated for the first time were bigger and better, respectively, than the average body size and body condition of the rejected males. There was a negative correlation between body sizes of first and second copulating males. This indicates that female mate choice is dependent on the previous mating history and it shows that the female's choice criteria are non-static, i.e. non-directional. Our study therefore suggests that context-dependent female mate choice may not only arise due to genotype-environment interactions, but also due to other female mating strategies, i.e. order-dependent mate choice. Thus context-dependent female mate choice might be more frequent than previously thought.

Performance of a chromatographic procedure used in the certification of reference material for polycyclic aromatic hydrocarbons in sewage sludge

Semi-automatic capillary gas chromatographic method with classical flame ionization detection, which satisfies the conditions for required performance and gave acceptable results within the framework of an interlaboratory certification programme for PAHs in sewage sludge, is described. The interesting feature of the procedure is that it incorporates automatic operations such as sample fractionation by semi-preparative HPLC, fraction collection at signal level recognition and evaporation under nitrogen flow. Multiple injections in the GC capillary column are performed in the on-column mode via an autosampler with temperature-programmable injector. Automatic data acquisition and chromatogram treatment are made via computer software. This partially automatic procedure releases personnel from tedious and time-consuming tasks and its robust character was validated through the certification of reference material for PAHs in sewage sludge, demonstrating its reliable performance.

Role of the serine protease CAP1/Prss8 and its inhibitor in the skin

The skin is the largest organ of the human body and protects it from water loss and mechanical damage. This barrier function is mainly provided by the epidermis, the outermost layer of the skin. This balance is regulated by several factors, including serine proteases, serine protease inhibitors and protease target substrates, such as receptors. Any mutations or alterations in the expression of these factors can lead to skin diseases. One of the players in this skin balance is the serine protease CAP1/Prss8, whose over-expression causes ichthyosis, hyperplasia and inflammation. This phenotype can be completely restored in the absence of PAR2 (protease-activated receptor 2) (Frateschi et al., 2011). During my thesis, I demonstrated that CAP1/Prss8 induces skin disease even if its catalytic triad is mutated. Additionally, I demonstrated an inhibitory effect of the serine protease-inhibitor nexin-1 (also called serpinE2, PN-1) on CAP1/Prss8, since nexin-1 negated the effects of both catalytically active and inactive CAP1/Prss8 over-expression. Indeed, CAP1/Prss8 and nexin-1 interact in vitro, but independent of the catalytic triad of CAP1/Prss8. These results demonstrate a novel mechanism of interaction between CAP1/Prss8 and nexin-1, and indicate that the catalytic triad of CAP1/Prss8 is dispensable for nexin-1 inhibition and PAR2 activation. These observations in vivo and in vitro could be helpful to specifically target drugs to treat ichthyoses-like skin diseases, like e.g. atopic dermatitis. - La peau est l'un des organes les plus importants du corps humain au regard de sa surface et de sa masse. Ses principales fonctions sont de nous protéger contre l'entrée de pathogènes et de former une barrière imperméable qui empêche la déshydratation. Ces fonctions sont principalement assurées par l'épiderme, la couche la plus superficielle de la peau, et garanties par plusieurs "acteurs", comme par exemple les sérine-protéases, les inhibiteurs de sérine- protéases ou les protéases cibles comme les récepteurs. Toute mutation ou altération de l'un de ces "acteurs" peut aboutir au déclanchement de maladies de la peau. Pour mieux comprendre les conséquences biologiques résultant d'une altération d'expression de CAP1/Prss8, une serine-protéase normalement exprimée au niveau de l'épiderme, nous avons généré des souris transgéniques surexprimant CAP1/Prss8 au niveau de la peau. Ces dernières présentent une peau squameuse, un épiderme hypertrophique, des processus inflammatoires et des prurits conséquents. Ces symptômes disparaissent si le gène du récepteur PAR2, qui régule l'activité des cellules de l'épiderme, est inactivé. Dans le but de vérifier si le phénotype observé chez les souris CAP1/Prss8 résulte de l'action du site catalytique de CAP1/Prss8, nous avons généré des souris CAP1/Prss8 chez lesquelles nous avons muté les trois acides aminés du site catalytique en alanine. Etonnement ces souris ont développé les mêmes problèmes de peau que les souris CAP1/Prss8, démontrant que l'effet de CAP1/Prss8, dans ce modèle animal, n'est pas lié à son site catalytique. Nous avons également montré in vivo, que la sérine-protéase nexin-1 (aussi appelée SERPINE2, PN-1) est capable d'exercer un effet inhibiteur sur CAP1/Prss8 indépendamment de l'activité du site catalytique de CAP1/Prss8. De plus, nous avons remarqué in vitro que CAP1/Prss8 et nexin-1 interagissent bien que la triade catalytique de CAP1/Prss8 soit enzymatiquement inactivée. Ces observations, in vivo et in vitro, pourraient être utilisées dans l'élaboration de médicaments contenant nexin-1, pour le traitement de pathologies de la peau telles l'ichthyose et la dermatite atopique.

Role of the epithelial sodium channel (ENaC) in the epidermal barrier function of the skin

Abstract In humans, the skin is the largest organ of the body, covering up to 2m2 and weighing up to 4kg in an average adult. Its function is to preserve the body from external insults and also to retain water inside. This barrier function termed epidermal permeability barrier (EPB) is localized in the functional part of the skin: the epidermis. For this, evolution has built a complex structure of cells and lipids sealing the surface, the stratum corneum. The formation of this structure is finely tuned since it is not only formed once at birth, but renewed all life long. This active process gives a high plasticity and reactivity to skin, but also leads to various pathologies. ENaC is a sodium channel extensively studied in organs like kidney and lung due to its importance in regulating sodium homeostasis and fluid volume. It is composed of three subunits α, ß and r which are forming sodium selective channel through the cell membrane. Its presence in the skin has been demonstrated, but little is known about its physiological role. Previous work has shown that αENaC knockout mice displayed an abnormal epidermis, suggesting a role in differentiation processes that might be implicated in the EPB. The principal aim of this thesis has been to study the consequences for EPB function in mice deficient for αENaC by molecular and physiological means and to investigate the underlying molecular mechanisms. Here, the barrier function of αENaC knockout pups is impaired. Apparently not immediately after birth (permeability test) but 24h later, when evident water loss differences appeared compared to wildtypes. Neither the structural proteins of the epithelium nor the tights junctions showed any obvious alterations. In contrary, stratum corneum lipid disorders are most likely responsible for the barrier defect, accompanied by an impairment of skin surface acidification. To analyze in details this EPB defect, several hypotheses have been proposed: reduced sensibility to calcium which is the key activator far epidermal formation, or modification of ENaC-mediated ion fluxes/currents inside the epidermis. The cellular localization of ENaC and the action in the skin of CAPl, a positive regulator of ENaC, have been also studied in details. In summary, this study clearly demonstrates that ENaC is a key player in the EPB maintenance, because αENaC knockout pups are not able to adapt to the new environment (ex utero) as efficiently as the wildtypes, most likely due to impaired of sodium handling inside the epidermis. Résumé Chez l'homme, la peau est le plus grand organe, couvrant presque 2m2 et pesant près de 4kg chez l'adulte. Sa fonction principale est de protéger l'organisme des agressions extérieures mais également de conserver l'eau à l'intérieur du corps. Cette fonction nommée barrière épithéliale est localisée dans la partie fonctionnelle de la peau : l'épiderme. A cette fin, l'évolution s'est dotée d'une structure complexe composée de cellules et de lipides recouvrant la surface, la couche cornée. Sa formation est finement régulée, car elle n'est pas seulement produite à la naissance mais constamment renouvelée tout au long de la vie, ce qui lui confère une grande plasticité mais ce qui est également la cause de nombreuses pathologies. ENaC est un canal sodique très étudié dans le rein et le poumon pour son importance dans la régulation de l'homéostasie sodique et la régulation du volume du milieu intérieur. Il est composé de 3 sous unités, α, ß et y qui forment un pore sélectif pour le sodium dans les membranes. Ce canal est présent dans la peau mais sa fonction n'y est pas connue. Des travaux précédents ont pu montrer que les souris dont le gène codant pour αENaC a été invalidé présentent un épiderme pathologique, suggérant un rôle dans la différentiation et pourrait même être impliqué dans la barrière épithéliale. Le but de cette thèse fut l'étude de la barrière dans ces souris knockouts avec des méthodes moléculaires et physiologiques et la caractérisation des mécanismes moléculaire impliqués. Dans ce travail, il a été montré que les souris mutantes présentaient un défaut de la barrière. Ce défaut n'est pas visible immédiatement à la naissance (test de perméabilité), mais 24h plus tard, lorsque les tests de perte d'eau transépithéliale montrent une différence évidente avec les animaux contrôles. Ni les protéines de structures ni les jonctions serrées de l'épiderme ne présentaient d'imperfections majeures. A l'inverse, les lipides de la couche cornée présentaient un problème de maturation (expliquant le phénotype de la barrière), certainement consécutif au défaut d'acidification à la surface de la peau que nous avons observé. D'autres mécanismes ont été explorées afin d'investiguer cette anomalie de la barrière, comme la réduction de sensibilité au calcium qui est le principal activateur de la formation de l'épiderme, ou la modification des flux d'ions entre les couches de l'épiderme. La localisation cellulaire d'ENaC, et l'action de son activateur CAPl ont également été étudiés en détails. En résumé, cette étude démontre clairement qu'ENaC est un acteur important dans la formation de la barrière épithéliale, car la peau des knockouts ne s'adapte pas aussi bien que celle des sauvages au nouvel environnement ex utero à cause de la fonction d'ENaC dans les mouvements de sodium au sein même de l'épiderme. Résumé tout public Chez l'homme, la peau est le plus grand organe, couvrant presque 2m2 et pesant près de 4kg chez l'adulte. Sa fonction principale est de protéger l'organisme des agressions extérieures mais également de conserver l'eau à l'intérieur du corps. Cette fonction nommée barrière épithéliale est localisée dans la partie fonctionnelle de la peau : l'épiderme. A cette fin, l'évolution s'est dotée d'une structure complexe composée de cellules et de lipides recouvrant la surface, la couche cornée. Sa formation est finement régulée, car elle n'est pas seulement produite à la naissance mais constamment renouvelée tout au long de la vie, ce qui lui confère une grande plasticité mais ce qui est également la cause de nombreuses maladies. ENaC est une protéine formant un canal qui permet le passage sélectif de l'ion sodium à travers la paroi des cellules. Il est très étudié dans le rein pour son importance dans la récupération du sel lors de la concentration de l'urine. Ce canal est présent dans la peau mais sa fonction n'y est pas connue. Des travaux précédents ont pu montrer que les souris où le gène codant pour αENaC a été invalidé présentent un épiderme pathologique, suggérant un rôle dans la peau et plus particulièrement la fonction de barrière de l'épiderme. Le but de cette thèse fut l'étude de la fonction de barrière dans ces souris mutantes, au niveau tissulaire et cellulaire. Dans ce travail, il a été montré que les souris mutantes présentaient une peau plus perméable que celle des animaux contrôles, grâce à une machine mesurant la perte d'eau à travers la peau. Ce défaut n'est visible que 24h après la naissance, mais nous avons pu montrer que les animaux mutants perdaient quasiment 2 fois plus d'eau que les contrôles. Au niveau moléculaire, nous avons pu montrer que ce défaut provenait d'un problème de maturation des lipides qui composent la barrière de la peau. Cette maturation est incomplète vraisemblablement à cause d'un défaut de mouvement des ions dans les couches les plus superficielles de l'épiderme, et cela à cause de l'absence du canal ENaC. En résumé, cette étude démontre clairement qu'ENaC est un acteur important dans la formation de la barrière épithéliale, car la peau des mutants ne s'adapte pas aussi bien que celle des sauvages au nouvel environnement ex utero à cause de la fonction d'ENaC dans les mouvements de sodium au sein même de l'épiderme.

New strategies in the modulation of fatty acid oxidation as a treatment for obesity

Strategies that enhance fat degradation or reduce caloricfood intake could be considered therapeutic interventions to reduce notonly obesity, but also its associated disorders. The enzyme carnitinepalmitoyltransferase 1 (CPT1) is the critical rate-determining regulatorof fatty acid oxidation (FAO) and might play a key role in increasingenergy expenditure and controlling food intake. Our group has shownthat mice overexpressing CPT1 in liver are protected from weight gain,the development of obesity and insulin resistance. Regarding foodintake control, we observed that the pharmacological inhibition ofCPT1 in rat hypothalamus decreased food intake and body weight.This suggests that modulation of CPT1 activity and the oxidation offatty acids in various tissues can be crucial for the potential treatmentof obesity and associated pathologies.

Concentration and estimated flow of soluble non-ammonia nitrogen entering the omasum of dairy cows as influenced by different protein supplements

Selostus: Valkuaistäydennyksen vaikutus lypsylehmän pötsistä virtaavan liukoisen rehuperäisen typen pitoisuuteen ja määrään sisärehuruokinnalla

Compliance with the Swiss Society for Nutrition's dietary recommendations in the population of Geneva, Switzerland: a 10-year trend study (1999-2009).

The trends in compliance with the dietary recommendations of the Swiss Society for Nutrition in the Geneva population were assessed for the period from 1999 to 2009 using 10 cross-sectional, population-based surveys (Bus Santé study) with a total of 9,320 participants aged 35 to 75 years (50% women). Dietary intake was assessed using a self-administered, validated, semi-quantitative food frequency questionnaire. Trends were assessed by logistic regression adjusting for age, smoking status, education, and nationality using survey year as the independent variable. After excluding participants with extreme intakes, the percentage of participants with a cholesterol intake of <300 mg/day increased from 40.8% in 1999 to 43.6% in 2009 for men (multivariate-adjusted P for trend=0.04) and from 57.8% to 61.4% in women (multivariate-adjusted P for trend=0.06). Calcium intake >1 g/day decreased from 53.3% to 46% in men and from 47.6% to 40.7% in women (multivariate-adjusted P for trend<0.001). Adequate iron intake decreased from 68.3% to 65.3% in men and from 13.3% to 8.4% in women (multivariate-adjusted P for trend<0.001). Conversely, no significant changes were observed for carbohydrates, protein, total fat (including saturated, monounsaturated, and polyunsaturated fatty acids), fiber, and vitamins D and A. We conclude that the quality of the Swiss diet did not improve between 1999 and 2009 and that intakes deviate substantially from expert recommendations for health promotion and chronic disease risk reduction.

Assessment of skinfold thickness equations in estimating body composition in children with inflammatory bowel

Introduction: Growth is a central process in paediatrics. Weight and height evaluation are therefore routine exams for every child but in some situation, particularly inflammatory bowel disease (IBD), a wider evaluation of nutritional status needs to be performed. The assessment of body composition is essential in order to maintain acceptable growth using the following techniques: Dual-energy X-ray absorptiometry (DEXA), bio-impedance-analysis (BIA) and anthropometric measurements (skinfold thickness skin), the latter being most easily available and most cost effective. Objectives: To assess the accuracy of skinfold equations in estimating percentage body fat (%BF) in children with inflammatory bowel disease (IBD), compared with assessment of body fat dual energy X-ray absorptiometry (DEXA). Methods: Twenty-one patients (11 females, 10 males; mean age: 14.3 years, range 12 - 16 years) with IBD (Crohn's disease n = 15, ulcerative colitis n = 6)). Estimated%BF was computed using 6 established equations based on the triceps, biceps, subscapular and suprailiac skinfolds (Deurenberg, Weststrate, Slaughter, Durnin & Rahaman, Johnston, Brook) and compared to DEXA. Concordance analysis was performed using Lin's concordance correlation and the Bland-Altman limits of agreement method. Results: Durnin & Rahaman's equation shows a higher Lin's concordance coefficient with a small difference amongst raw values for skinfolds and DEXA compared to the other equations. Correlation coefficient between mean and difference is close to zero with a non-significant Bradley-Blackwood test. Conclusion: Body composition in paediatric IBD patients using the Durnin & Rahaman skinfold-equation adequately reflects values obtained by DEXA.

Short-term, mixed-diet overfeeding in man: no evidence for "luxuskonsumption".

After 13 days of weight maintenance diet (13,720 +/- 620 kJ/day, 40% fat, 15% protein, and 45% carbohydrate), five young men (71.3 +/- 7.1 kg, 181 +/- 8 cm; means +/- SD) were overfed for 9 days at 1.6 times their maintenance requirements (i.e., +8,010 kJ/day). Twenty-four-hour energy expenditure (24-h EE) and basal metabolic rate (BMR) were measured on three occasions, once after 10 days on the weight-maintenance diet and after 2 and 9 days of overfeeding. Physical activity was monitored throughout the study, body composition was measured by underwater weighing, and nitrogen balance was assessed for 3 days during the two experimental periods. Overfeeding caused an increase in body weight averaging 3.2 kg of which 56% was fat as measured by underwater weighing. After 9 days of overfeeding, BMR increased by 622 kJ/day, which could explain one-third of the increase in 24-h EE (2,038 kJ/day); the remainder was due to the thermic effect of food (which increased in proportion with excess energy intake) and the increased cost of physical activity, related to body weight gain. This study shows that approximately one-quarter of the excess energy intake was dissipated through an increase in EE, with 75% being stored in the body. Under our experimental conditions of mixed overfeeding in which body composition measurements were combined with those of energy balance, it was possible to account for all of the energy ingested in excess of maintenance requirements.

Predicting the mating system from phenotypic correlations between life-history and sperm quality traits in the Alpine whitefish Coregonus zugensis

The mating behavior and reproductive strategies of Alpine whitefish like Coregonus zugensis (Nusslin) are poorly understood, probably because they spawn in deep water where direct observations are difficult. In this study, we interpret life-history and sperm quality traits of fish that we caught from their spawning place. We found that males invest heavily into gonadal tissue (up to 5.6% of their body weight), which is, in comparison to other fish, consistent with external fertilization, distinct pairing and moderate to high communal spawning, or no pairing and low to moderate communal spawning. Sperm competition theory and recent experimental studies on other salmonids predict that males optimize ejaculate characteristics in relation to the costs of sperm and the level of competition they have to expect: dominant males are predicted to invest less into ejaculate quality and to have slower spermatozoa than subdominant males. We found that spermatozoa of older males are slower than those of younger males. Moreover, older males have larger breeding tubercles, a secondary sexual trait that has, in some previous studies, been found to be linked to good condition and to good genetic quality. Our results suggest that C. zugensis has age-linked reproductive strategies, that multimale spawning is common, i.e., that sperm competition plays a significant role, and that older males are on average dominant over younger males at the spawning place.

Fecundity versus offspring size in the greater white-toothed shrew Crocidura russula

1. The relationships between female body mass (WWal)i, tter size (m), juvenile growth rate (G) and mass at weaning (W20) were examined by monitoring natural litters in 29 greater white-toothed shrews, Crocidura russula (Hermann 1780). The trade-offs between m and G or W20 were further investigated by manipulating litter sizes: each of seven females reared four litters of 2, 4, 6 and 8 offspring. 2. Offspring mass at weaning (W20) exhibited a large variance, most of which could be attributed (ANCOVA on manipulated litters) to two effects: a litter-size effect, and a female individual effect, referred to as 'female quality'. 3. Litter size explained 68% of the variance in W20 among manipulated litters (linear regression). The limited milk supply was probably responsible for this effect, because litter size depressed growth rate during the first half of the lactation period (G1), but not during the weaning stage (G2). 4. Among non-manipulated litters, litter size correlated positively with maternal body mass (Wa), so that large females tended to produce small juveniles. This correlation between m and Wa is seen as the result of a body-mass dependence in the cost of raising a litter of a given size, during either pregnancy or lactation. 5. Differences in 'female quality' explained 16% of the variance in W20 among manipulated litters. This factor did not affect GI and may thus relate to differences among offspring of different females in their rates of processing milk and/or external food during late lactation. 6. 'Female quality' was independent of both body mass and litter size: larger females did not produce larger offspring when controlled for litter size, while higher-quality females did not produce larger litters. 7. Our results support the hypothesis that most variance in adult and juvenile body masses is non-genetic, and stems from the trade-off between litter size and offspring size.

Adipose reduction in the activity of the repressor ICER is responsible for insulin resistance elicited by the transcriptional factors CREB in obesity

BACKGROUND AND AIMS: Sustained adipose activation of the transcriptional activators cAMP response binding proteins (CREB) in obesity leads to impaired expression of the glucose transporter GLUT4 and adiponectin (adipoq) in mice model of obesity. Diminution of GLUT4 and adipoq caused by CREB is indirect and relies on the increased repressive activity of the CREB target gene activating transcription factor 3 (ATF3). Specific inactivation of CREB in adipocytes decreases ATF3 production and improves whole-body insulin sensitivity of mice in the context of diet-induced obesity. Thus, elevation of CREB activity is a key mechanism responsible for adipocyte dysfunction and systemic insulin resistance. The inducible cAMP early repressor (ICER) is a negative regulator of the CREB activity. In fact, ICER antagonizes the CREB factor by competing for the regulation of similar target genes. The goal of the study was to investigate whether loss of ICER expression in adipocytes could be responsible for increased CREB activity in obesity. MATERIALS AND METHODS: Mice C57bl6 were fed with a high fat diet (HFD) for 12 weeks to increase body weight and generate insulin resistance. Biopsies of visceral adipose tissues (VAT) were prepared from human lean (BMI=24}0.5 Kg/m2) or obese subjects (BMI>35 Kg/m2). Total RNA and protein were prepared from white adipose tissues (WAT) of chow- or HFD-fed mice and VAT of lean and obese subjects. Activities of CREBs and ICER were monitored by electromobility shift assays (EMSA). The role of ICER on CREB activity was confirmed in 3T3-L1 adipocytes cells. Briefly after differentiation, the cells were electroporated with the plasmid coding for ICER cDNA. Gene expression was quantified by quantitative real-time PCR and western Blotting experiments. RESULTS: The expression of ICER is reduced in WAT of HFD-induced obese mice when compared to chow mice as measured by real-time PCR and EMSA. Similar result was found in human tissues. Reduction in ICER expression was associated with increased ATF3 expression and decreased adipoq and GLUT4 contents. Diminution in ICER levels was observed in adipocytes fraction whereas its expression was unchanged in stroma vascular fraction of WAT. Overexpression of ICER in 3T3-L1 adipocytes silenced the expression of ATF3, confirming the regulation of the factor by ICER. The expression of ICER is regulated by histone deacetylases activity (HDAC). Inhibition of HDACs in 3T3-L1 adipocytes cells using trichostatin inhibited the production of ICER. The whole activity of HDAC was reduced in WAT and VAT of obese mice and human obese subjects. CONCLUSION: Impaired adipose expression of ICER is responsible of increased CREB activity in adipocytes in obesity. This mechanism relies on reduction of the HDAC activity.