OBJECTIVEObesity alters gut microbiota ecology and associates with low-grade inflammation in humans. Roux-en-Y gastric bypass (RYGB) surgery is one of the most efficient procedures for the treatment of morbid obesity resulting in drastic weight loss and improvement of metabolic and inflammatory status. We analyzed the impact of RYGB on the modifications of gut microbiota and examined links with adaptations associated with this procedure.RESEARCH DESIGN AND METHODSGut microbiota was profiled from fecal samples by real-time quantitative PCR in 13 lean control subjects and in 30 obese individuals (with seven type 2 diabetics) explored before (M0), 3 months (M3), and 6 months (M6) after RYGB.RESULTSFour major findings are highlighted: 1) Bacteroides/Prevotella group was lower in obese subjects than in control subjects at M0 and increased at M3. It was negatively correlated with corpulence, but the correlation depended highly on caloric intake; 2) Escherichia coli species increased at M3 and inversely correlated with fat mass and leptin levels independently of changes in food intake; 3) lactic acid bacteria including Lactobacillus/Leuconostoc/Pediococcus group and Bifidobacterium genus decreased at M3; and 4) Faecalibacterium prausnitzii species was lower in subjects with diabetes and associated negatively with inflammatory markers at M0 and throughout the follow-up after surgery independently of changes in food intake.CONCLUSIONSThese results suggest that components of the dominant gut microbiota rapidly adapt in a starvation-like situation induced by RYGB while the F. prausnitzii species is directly linked to the reduction in low-grade inflammation state in obesity and diabetes independently of calorie intake.

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of sc-WAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56؉/CD68؉; 22.6 ؎ 4.3 vs. 1.4 ؎ 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (؊11.63 ؎ 2.3%, P < 0.

Background: Investigations performed in mice and humans have acknowledged obesity as a lowgrade inflammatory disease. Several molecular mechanisms have been convincingly shown to be involved in activating inflammatory processes and altering cell composition in white adipose tissue (WAT). However, the overall importance of these alterations, and their long-term impact on the metabolic functions of the WAT and on its morphology, remain unclear.

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα cells with high CD9 expression (CD9) originates pro-fibrotic cells whereas their CD9 counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRαCD9 fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9 progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

Objective. Previous studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with wellcharacterized PAN diagnoses.Methods. We conducted a systematic retrospective study of 348 patients who were diagnosed as having Multivariate analysis retained age >65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse.Conclusion. Our findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.Polyarteritis nodosa (PAN), first described in 1866 by Küssmaul and Maier (1), is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries, and is primary in most patients but is the consequence of viral infections, mainly hepatitis B virus (HBV), in some. Populations of patients with PAN that

White adipose tissue (WAT) in obese humans is characterized by macrophage accumulation the effects of which on WAT biology are not fully understood. We previously demonstrated that macrophage-secreted factors impair preadipocyte differentiation and induce inflammation, and we described the excessive fibrotic deposition in WAT from obese individuals. Microarray analysis revealed significant overexpression of extracellular matrix (ECM) genes in inflammatory preadipocytes. We show here an organized deposition of fibronectin, collagen I, and tenascin-C and clustering of the ECM receptor alpha5 integrin, characterizing inflammatory preadipocytes. Anti-alpha5 integrin-neutralizing antibody decreased proliferation of these cells, underlining the importance of the fibronectin/integrin partnership. Fibronectin-cultured preadipocytes exhibited increased proliferation and expression of both nuclear factor-kappaB and cyclin D1. Small interfering RNA deletion of nuclear factor-kappaB and cyclin D1 showed that these factors link preadipocyte proliferation with inflammation and ECM remodeling. Macrophage-secreted molecules increased preadipocyte migration through an increase in active/phosphorylated focal adhesion kinase. Gene expression and neutralizing antibody experiments suggest that inhibin beta A, a TGF-beta family member, is a major fibrotic factor. Interactions between preadipocytes and macrophages were favored in a three-dimensional collagen I matrix mimicking the fibrotic context of WAT. Cell-rich regions were immunostained for preadipocytes, proliferation, and macrophages in the vicinity of fibrotic WAT from obese individuals. In conclusion, an inflammatory environment leads to profound modifications of the human preadipocyte phenotype, producing fibrotic components with increased migration and proliferation. This phenomenon might play a role in facilitating the constitution of quiescent preadipocyte pools and eventually in the maintenance and aggravation of increased fat mass in obesity.

BackgroundIn humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear.ObjectivesWe characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters.MethodsSeventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women.ResultsPOP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6–12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index.ConclusionsPOP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden.

Objective. To analyze hematopoietic and immune reconstitution after autologous hematopoietic stem cell transplantation (HSCT) in 7 patients with systemic sclerosis (SSc).Methods. Two groups of patients were retrospectively constituted according to whether they had a favorable clinical response (group A; n ‫؍‬ 4) or no response or a relapse of disease (group B; n ‫؍‬ 3) after HSCT. Immune reconstitution was analyzed every 3 months using lymphocyte immunophenotyping, ␣/␤ T cell receptor (TCR) diversity analysis, and ex vivo thymic function analysis by quantification of TCR rearrangement excision circles (TRECs).Results. Patients had similar characteristics at study entry, except for a lower modified Rodnan skin thickness score (P ‫؍‬ 0.03) and a lower Health Assessment Questionnaire score (P ‫؍‬ 0.05) in group A than in group B. The number of reinjected cells and the time to hematopoietic reconstitution were similar in both groups. The absolute numbers of CD19؉ and CD20؉ B cells were lower in group A than in normal controls (P < 0.05) and within the normal range in group B. Absolute numbers of T and natural killer lymphocytes were normal before HSCT. Numbers of CD3؉ cells remained low thereafter. Numbers of CD8؉ cells were back to normal 3 months after HSCT in both groups. B cell counts were low until 6 months after HSCT in group A and stayed in the normal range in group B. The CD3؉ defect was sustained in group A, with an opposite trend and a faster CD4؉ reconstitution profile in group B. The T cell repertoire was skewed before and until 1 year after HSCT, with shared expansions before and after transplant in a given individual. TREC values correlated negatively with C-reactive protein levels (r s ‫؍‬ ؊0.41, P ‫؍‬ 0.001) and positively with CD19؉ (r s ‫؍‬ 0.35, P ‫؍‬ 0.001) and CD20؉ (r s ‫؍‬ 0.34, P ‫؍‬ 0.002) lymphocyte counts.Conclusion. B and T lymphocyte populations remained disturbed for at least 1 year after HSCT in SSc patients, which may reflect the persistence of an underlying disease mechanism.Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by excessive collagen deposition within the skin and internal organs (1). Although its exact pathogenesis remains unknown, predominant T cell activation (2), production of autoantibodies (includ-