Brown Adipose Tissue Thermogenic Capacity Is Regulated by Elovl6.

Although many transcriptional pathways regulating BAT have been identified, the role of lipid biosynthetic enzymes in thermogenesis has been less investigated. Whereas cold exposure causes changes in the fatty acid composition of BAT, the functional consequences of this remains relatively unexplored. In this study, we demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) is necessary for the thermogenic action of BAT. Elovl6 is responsible for converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does not modulate traditional BAT markers; instead, it causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity. The reduction in BAT activity appears to be counteracted by increased beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6 KO mice gain weight and have increased scWAT mass and impaired carbohydrate metabolism. Overall, our study suggests fatty acid chain length is important for BAT function.We thank the BBSRC, MRC, EU FP7 5 BetaBAT and Wellcome Trust for funding this work.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.11.00

Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity.

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs

Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice.

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.The work was also supported by Diabetes UK and the MRC [G1002610]. VP held an Arthur and Sadie Pethybridge PhD Studentship from Diabetes UK. The CIMR microscopy core facility is supported by a Wellcome Trust Strategic Award [100140] and a Wellcome Trust equipment grant [093026]

Chemins de vie. Dix-neuf visages et paroles de migrant-e-s, 1956-2012

Dix-neuf entretiens avec des migrant-e-s ont été réalisés et analysés par des étudiant-e-s du Master d’histoire moderne et contemporaine des Universités Lyon 2 et Lyon 3.Ces migrant-e-s appartiennent à diverses générations (le plus âgé, Ferdinand Gonzalez, est née en 1935 et la plus jeune, Anaïs Quenette, en 1995) et sont d’origines géographiques variées (Europe, Afrique du Nord et subsaharienne, Amérique latine…). Ce sont des femmes et hommes qui ont émigré en France pour des raisons de travail, mais aussi pour suivre leurs parents, rejoindre un-e conjoint-e ou simplement pour faire des études supérieures. Certain-e-s ont demandé leur naturalisation, d’autres pas.Le fil rouge qui a été choisi pour structurer les entretiens est celui de « l’insertion » envisagée sous diverses facettes : le départ et les réactions de l’entourage, les représentations liées à la France, mais aussi les réactions des Françaises face à l’Autre, l’insertion sur le marché du travail, l’apprentissage de la langue, le logement comme les différents réseaux tissés dans l’exil, les différentes identités induites et bousculées par la migration.Le volume est organisé en deux parties. La première est l’analyse des entretiens en six grandes thématiques. La deuxième partie regroupe la retranscription intégrale des entretiens menés, qui sont classés par ordre alphabétique des noms de famille, qui peuvent être des pseudonymes. Les retranscriptions sont précédées de quelques lignes méthodologiques sur les conditions de l’entretien

Management of lower urinary tract fibroepithelial polyps in children

Introduction Fibroepithelial polyps (FEP) of the lower urinary tract are relatively common in adults but rare in children, with fewer than 250 cases reported in the literature to date. Objective The aim of this study was to address the experience of FEP management in children. Study design A retrospective multicenter review was undertaken in children with defined FEP of the lower urinary tract managed between 2008 and 2018. The data at 18 pediatric surgery centers were collected. Their demographic, radiological, surgical, and pathological information were reviewed. Results A total of 33 children (26 boys; 7 girls) were treated for FEP of the lower urinary tract at 13 centers. The most common presentation was urinary outflow as hematuria (41%), acute urinary retention (25%), dysuria (19%), or urinary infections (28%). A prenatal diagnosis was made for three patients with hydronephrosis. Almost all of the children (94%) underwent ultrasound imaging of the urinary tract as the first diagnostic examination, 23 (70%) of them also either had an MRI (15%), cystourethrography (25%), computerized tomography (6%), or cystoscopy (45%). Two of these children (6%) had a biopsy prior to the surgery. The median preoperative delay was 7.52 (range: 1–48) months. Most of the patients were treated endoscopically, although four (12.1%) had open surgery and two (6.1%) had an additional incision for specimen extraction. The median hospital stay was 1.5 (range: 1–10) days. There were no recurrences and no complications after a median follow-up of 13 (range: 1–34) months. Discussion The main limitation of our study is the retrospective design, although it is the largest one for this pathology. Conclusion This series supports sonography as the most suitable diagnosis tool before endoscopy to confirm the diagnosis and to perform the resection for most FEP in children. This report confirms the recognized benign nature in the absence of recurrences

Etude cellulaire des syndromes lipodystrophiques et progéroïdes liés aux mutations du gène lmna (résistance à l insuline et dysfonction endothéliale)

la lipodystrophie partielle familiale de dunnigan (fpld2) ou la progéria de hutchinson-gilford (hgps), syndrome de vieillissement accéléré, sont dues à des mutations du gène lmna, codant les lamines de type a. elles partagent certaines atteintes : lipodystrophie, résistance à l insuline et athérosclérose précoce. elles mettent en lumière les liens étroits entre atteintes métaboliques, vieillissement et maladies cardiovasculaires. au cours de ma thèse, je me suis intéressé aux mécanismes cellulaires impliqués dans la résistance à l insuline et la dysfonction endothéliale, qui participeraient aux atteintes métaboliques et cardiovasculaires. les effets des mutations conduisant à la fpld2 et l hgps sur la signalisation insulinique ont été étudiés dans des cellules ovariennes de hamster surexprimant de façon stable le récepteur de l insuline. seule la surexpression de la mutation responsable de l hgps entraine une résistance à l insuline cellulaire. ainsi, la résistance à l insuline serait secondaire à la lipodystrophie et au défaut de stockage du tissu adipeux chez les patients fpld2. Nous avons confirmé la forte prévalence d évènements cardiovasculaires chez les patients fpld2. de plus, la surexpression des mutations de lamine a associées à la fpld2 ou à l hgps induisent une dysfonction endothéliale, initiatrice du processus d athérosclérose. Nos données suggèrent un mécanisme commun : l accumulation des précurseurs farnésylés de la lamine a entrainerait un stress oxydant, responsable de leurs effets toxiques. un impact direct de certaines mutations du gène lmna sur les fonctions vasculaires et métaboliques est envisageable et ouvre de nouvelles pistes thérapeutiquessome mutations in the lmna gene, encoding a-type lamins, lead to the dunnigan-type familial partial lipodystrophy (fpld2) or to the premature aging syndrome hutchinson-gilford progeria (hgps). these diseases share some features such as lipodystrophy, insulin resistance and early atherosclerosis. they highlight the complex relationship between metabolic alterations, aging and cardiovascular diseases. During my phd, i studied the cellular mechanisms involved in insulin resistance and endothelial dysfunction, which could participate to the development of metabolic and cardiovascular alterations. The effects on insulin signalling of the mutated lamins a linked with fpld2 and hgps were analysed in chinese hamster ovary cells stably overexpressing the insulin receptor. only the exogenous expression of the mutation associated with hgps trigger cellular insulin resistance. therefore, the insulin resistance developed by fpld2 patients could be secondary to the inability of the atrophied adipose tissue to correctly store fatty acids. We confirmed the high prevalence of clinical cardiovascular events in fpld2 patients. in addition, the overexpression of mutated lamins associated with fpld2 or hgps led to in vitro human coronary endothelial cells dysfunction, which initiates atherogenesis. Interestingly, our data suggest a common cellular mechanism, : the accumulation of farnesylated lamin a precursors could lead to oxidative stress that triggers their toxic effects. these data suggest a direct impact of some lmna mutations in the development of metabolic and cardiovascular diseases and give new insights in the challenge of these diseasesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells

International audienceHutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients' endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin-zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases

Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice.

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.The work was also supported by Diabetes UK and the MRC [G1002610]. VP held an Arthur and Sadie Pethybridge PhD Studentship from Diabetes UK. The CIMR microscopy core facility is supported by a Wellcome Trust Strategic Award [100140] and a Wellcome Trust equipment grant [093026]

CT-scan prediction of thyroid cartilage invasion for early laryngeal squamous cell carcinoma

International audienc

Dietary (Poly)phenols, Brown Adipose Tissue Activation, and Energy Expenditure: A Narrative Review.

The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted