Adipocyte ATP-binding cassette G1 promotes triglyceride storage, fat mass growth, and human obesity

The role of ATP-binding Cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of Lipoprotein Lipase (LPL).As both ABCG1 and LPL are expressed in adipose tissue, we hypothesize that ABCG1 is implicated in adipocyte TG storage and could be then a major actor in adipose tissue fat accumulation.Silencing of Abcg1 expression by RNAi in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during initial phase of differentiation. Generation of stable Abcg1 Knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 SNPs (rs1893590 (A/C) and rs1378577 (T/G)) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with an increased PPARγ expression and adiposity concomitant to an increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 regarding obesity was further confirmed in independent populations of severe obese and diabetic obese individuals.For the first time, this study identifies a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity

Détection des modifications du comportement d`un bassin versant : une approche qui s`appuie sur la modélisation. Application aux conditions non stationnaires d`Afrique de l`Ouest

West Africa has been subject to changing climatic and hydrologic conditions during the second half of the last century. The Upper Ouémé catchment (10.050 km2, Benin) case study is characteristic, since a large reduction in rainfall has been affecting the region since the seventies, and land-cover has been modified by the growth of anthropic pressure and agricultural surfaces. In these conditions, can we detect a modification of the hydrological behaviour of the catchment? This study proposes a model-based framework to detect hydrological changes, taking into account modelling uncertainties. Hence, use is made of a daily lumped hydrological model (GR4J, Perrin & al. 2003). First, the daily rainfall and discharge data-set collected on the Upper Ouémé since 1954 has been analysed. Statistical tests on the annual runoff rate point out the changes in the catchment behaviour around 1970. Secondly, the model was calibrated on different 17-years time periods, using a resampling technique. Because of the weakness of the parameter specification process, changes in hydrological behaviour can not be linked with changes in parameter values, since a large natural variability occurs. However, the relevance of the 1970 break point is shown from year to year calibration results. In order to take into account the parameters estimation uncertainty, an alternative approach, based on the GLUE methodology, has been developed. This approach is shown to give far more understandable results, and allows finding the signature of hydro-climatic variability, both in the model structure (parameter values) and the model outputs (simulated runoff).L`Afrique de l`Ouest est soumise, depuis la seconde moitié du 20ème siecle, à un changement des conditions climatiques et hydrologiques. Le haut-bassin de l`Ouémé (10050 km2, Bénin) en est un exemple caractéristique puisque, depuis les années 70, une forte diminution des précipitations y est observé, ainsi qu`une pression anthropique grandissante sur les surfaces agricoles. Dans de telles conditions, est-il possible de détecter une modification du comportement hydrologique du bassin versant ? Cette étude propose une méthode pour aborder cette question, fondée sur la modélisation et prenant en compte les incertitudes dans la modélisation. On utilise un modèle hydrologique global (GR4J, Perrin et al., 2003). Dans un premier temps, les données collectées sur le haut-bassin de l`Ouémé depuis 1954 ont été analysées. Des tests statistiques sur la série de débits met en évidence un changement du comportement du bassin au environs des années 1970. Dans un deuxième temps, le modèle a été calibre sur 17 années, à partir d`une technique de ré-échantillonnage. A cause de la non robustesse de la spécification des paramètres, les modifications du comportement hydrologique du bassin ne peuvent être reliées à un changement des valeurs de paramètres, puisque une grande variabilité naturelle est présente. Néanmoins, à partir d`une calibration année par année, on a pu montrer la pertinence de la date de changement en 1970. Afin de prendre en compte les incertitudes dans l`estimation des paramètres, une approche alternative, s`appuyant sur la méthode GLUE, a été développée. On montre que cette approche conduit à des résultats plus faciles à interpréter et permet une meilleure appréhension de la variabilité hydro-climatique, à la fois sur la structure du modèle (valeurs des paramètres) et sur ses simulations (débits simulés)

HIF2α is a direct regulator of neutrophil motility.

Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2α) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes