Dysfonction des tissus adipeux : médiateurs inflammatoires et effets de la chirurgie bariatrique

L’obésité est un important facteur de risque de maladies métaboliques et cardiovasculaires. En présence d’un bilan énergétique positif, un remodelage inadéquat des tissus adipeux semble jouer un rôle déterminant dans l’apparition des altérations cardiométaboliques reliées à l’excès de masse grasse. La dysfonction adipeuse associée à ce remodelage pathologique se caractérise entre autres par une capacité de stockage altérée des graisses (incapacité à générer suffisamment de nouveaux adipocytes/adipogenèse altérée, hypertrophie adipocytaire et accumulation excessive de graisse au niveau viscéral), une augmentation du nombre de cellules immunitaires infiltrant le tissu adipeux et une hypersécrétion de cytokines pro-inflammatoires. L’objectif général du présent mémoire était d’examiner les modulateurs de la dysfonction adipeuse tels que l’IL-1β, les enzymes de synthèse des prostaglandines et la chirurgie bariatrique. Afin de réaliser cet objectif, nous avons d’abord examiné l’impact de l’IL-1β et de certaines enzymes de synthèse des prostaglandines (COX-2 et AKR1B1) sur divers marqueurs reliés à l’inflammation et à l’adipogenèse chez l’humain, et ce, à partir d’échantillons de tissus adipeux omental et sous-cutané. Nous avons également effectué une revue de la littérature qui décrit les conséquences de la perte de poids induite par la chirurgie bariatrique sur l’infiltration des macrophages et sur la sécrétion d’un large spectre de médiateurs anti-ou pro-inflammatoires. Nos résultats révèlent que l’IL-1β induit une réponse pro-inflammatoire dans les tissus adipeux humains, particulièrement dans le dépôt viscéral, et agit indépendamment de la libération concomitante de prostaglandines. L’IL-1β et COX-2 semblent également être des déterminants critiques du remodelage pathophysiologique du tissu adipeux lors du développement de l’obésité, en modulant négativement le processus d’adipogenèse. De plus, les études montrent généralement que la chirurgie bariatrique peut renverser l'infiltration des macrophages et les altérations du profil sécrétoire qui sont observées dans le tissu adipeux des patients qui souffrent d'obésité. En conclusion, nos travaux montrent que l’IL-1β et COX-2 pourraient être impliqués dans le développement de la dysfonction adipeuse, alors que la chirurgie bariatrique semble être une stratégie anti-inflammatoire efficace permettant de renverser, du moins en partie, la dysfonction des tissus adipeux abdominaux.Obesity is an important risk factor of metabolic and cardiovascular disease development. Under a positive energy imbalance, inadequate adipose tissue remodeling appears to play a determinant role in the onset of cardiometabolic alterations associated with excess fat mass. Adipose tissue dysfunction, related to this pathological remodeling, is characterized by altered fat storage capacity (altered capacity to generate new adipocytes/altered adipogenesis, adipocyte hypertrophy, excessive accumulation of visceral fat), increased number of immune cells infiltrating adipose tissue and oversecretion of pro-inflammatory cytokines. The overall objective of this master’s thesis was to examine modulators of adipose tissue dysfunction, such as IL-1β, prostaglandin-synthesizing enzymes and bariatric surgery. To achieve this objective, we first examined the impact of IL-1βand prostaglandin-synthesizing enzymes (COX-2 and AKR1B1) on markers related to inflammation and adipogenesis in human omental and subcutaneous adipose tissue samples. We also reviewed available literature documenting the impact of surgery-induced weight loss on macrophage infiltration and on the secretion of a broad spectrum of anti-or pro-inflammatory mediators. Our results show that IL-1β induces a pro-inflammatory response in human adipose tissues, particularly in visceral fat, and acts independently of concomitant prostaglandin release. IL-1β and COX-2 also appear to be critical determinants of adipose tissue pathophysiologic remodeling in obesity, in negatively modulating adipogenesis. Furthermore, reports generally show that bariatric surgery reverses both macrophage infiltration and the altered secretory profile observed in the adipose tissue of patients with obesity. In conclusion, we demonstrated that IL-1β and COX-2could be implicated in the development of adipose tissue dysfunction, although data enable us to describe bariatric surgery as a successful anti-inflammatory strategy, which could partly reverse abdominal adipose tissue dysfunction

Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction

Obesity is a heterogeneous disease and is associated with comorbidities such as type 2 diabetes mellitus, cardiovascular disease and cancer. Several studies have examined the role of dysfunctional adipose tissue in the pathogenesis of obesity, highlighting the contrasting properties and impact of distinct fat compartments, sometimes with contradictory results. Dysfunctional adipose tissue involves enlargement, or hypertrophy, of pre-existing fat cells, which is thought to confer increases in cardiometabolic risk, independent of the level of obesity per se . In this article, we critically analyze available literature that examined the ability of adipocyte cell size to predict metabolic disease and adipose tissue dysfunction in humans. Many studies demonstrate that increased fat cell size is a significant predictor of altered blood lipid profiles and glucose–insulin homeostasis independent of adiposity indices. The contri- bution of visceral adiposity to these associations appears to be of particular importance. However, available studies are not unanimous and many fat depot-specific aspects of the relationship between increased fat cell size and cardiometabolic risk or parameters of adipose tissue dysfunction are still unresolved. Methodological factors such as the approach used to express the data may represent significant confounders in these studies. Additional studies should consider the fact that the relationship between fat cell size and common adiposity indices is non-linear, particularly when reaching the obese range. In conclusion, our analysis demonstrates that fat cell size is a significant predictor of the cardiometabolic alterations related to obesity. We propose that adipocyte hypertrophy, especially in the visceral fat compartment, may represent a strong marker of limited hyperplasic capacity in subcutaneous adipose tissues, which in turn is associated with the presence of numerous cardiometabolic alterations

Interleukin-1β and prostaglandin-synthesizing enzymes as modulators of human omental and subcutaneous adipose tissue function

IL-1β stimulates expression of prostaglandin (PG)-synthesizing enzymes cyclooxygenase (COX)-2 and aldo-keto reductase (AKR)1B1 in human preadipocytes. We aimed to examine the impact of IL-1β, COX-2 and AKR1B1 on markers of human visceral and subcutaneous adipose tissue function, and to assess whether PG synthesis by these enzymes mediates IL-1β effects. Omental and subcutaneous fat samples were obtained from bariatric surgery patients. PG release and expression of inflammatory and adipogenic markers were assessed in explants treated with COX-2 inhibitor NS-398 or AKR1B1 inhibitor Statil, with or without IL-1β. Preadipocyte differentiation experiments were also performed. IL-1β decreased expression of PPAR in both fat depots compared to control and increased expression of NF- B1, IL-6, CCL-5, ICAM-1 and VEGFA, especially in visceral fat for IL-6, CCL-5 and VEGFA. Adding Statil or NS-398 to IL-1β blunted PGF2α and PGE2 release, but did not alter IL-1β effects on adipose tissue function markers. IL-1β down-regulated adipocyte differentiation whereas NS-398 alone increased this process. However, NS-398 did not prevent IL-1β inhibition of adipogenesis. We conclude that IL-1β induces a pro-inflammatory response in human adipose tissues, particularly in visceral fat, and acts independently of concomitant PG release. IL-1β and COX-2 appear to be critical determinants of adipose tissue pathophysiologic remodeling in obesity

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS.BackgroundHepatitis B (HBV) historically has been a public health issue within hemodialysis units. This study estimates HBV prevalence and seroconversion rates across seven countries and investigates associations with facility level practice patterns.MethodsThe study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a cross-sectional, prospective, observational study of adult hemodialysis patients randomly selected from 308 dialysis facilities in France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States. Logistic regression was used to model the odds ratio (OR) of HBV prevalence, and Cox regression was used to model time from entry into the study to HBV seroconversion.ResultsIn this sample, mean HBV facility prevalence was 3.0% with a median of 1.9%. The percentage of facilities with an HBV prevalence 0% to 5% was 78.5%. Adjusted HBV prevalence was higher in France, Germany, and Italy and lower in Japan and the United Kingdom. The majority of facilities (78.1%) had a seroconversion rate of 0 conversions per 100 patient-years. Presence of a protocol for HBV-infected patients was significantly associated with HBV seroconversion in the separate practice pattern model [risk ratio (RR) = 0.52, P = 0.03] and in the combined practice pattern model (RR = 0.44, P = 0.01).ConclusionThere are differences in HBV prevalence and rate of seroconversion both at the country and the hemodialysis facility level. Presence of a protocol for HBV-infected patients was strongly and significantly associated with decreased risk for seroconversion. The observed variation suggests opportunities for improved HBV outcomes with further definition of optimal practice patterns at the facility level

Cancer risk in childhood-onset systemic lupus

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care