Meriem Abdennour

CD14dimCD16+ and CD14+CD16+ Monocytes in Obesity and During Weight Loss

Objective—Studies suggest the implication of CD16+ subpopulations (CD14+CD16+, CD14dimCD16+) in inflammatory diseases. We aimed to determine the frequency of these subpopulations during weight loss in obesity and diabetes, conditions associated with changes in systemic inflammation, and we tested the link with subclinical atherosclerosis. Methods and Results—CD14dimCD16+ and CD14+CD16+ frequencies were measured by flow cytometry in lean subjects, obese subjects before and after a hypocaloric diet or gastric surgery, and obese diabetic subjects before and after gastric surgery. Both monocyte subsets were increased in obese subjects, with a significant enrichment of the CD14dimCD16+ subpopulation in obese diabetic patients. Multivariate analysis demonstrated a link between the percentages of CD14dimCD16+ monocytes and glycemia, independent of fat mass. Drastic weight loss led to a sharp decrease of this subset, the variations of which were strongly related to fat mass changes. A reduction of at least 5% of fat mass was sufficient to observe a significant decrease of CD14dimCD16+ monocytes. A diminution of the CD14+CD16+ subset was also observed during weight loss and was associated with a decrease in intima-media thickness. Conclusion—This work demonstrates a major impact of fat mass variations on CD14dimCD16+ monocyte subsets and that the decrease in the CD14+CD16+ subpopulation is linked to a reduction of subclinical atherosclerosis. Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique identifier: NCT00476658.

Variations in circulating inflammatory factors are related to changes in calorie and carbohydrate intakes early in the course of surgery-induced weight reduction.

BACKGROUND Obesity is considered a low-grade inflammatory state that improves with weight loss. In addition to acute-phase proteins, other cytokines might contribute to systemic inflammation. OBJECTIVE Our objective was to compare serum concentrations of a large panel of inflammation-related factors in obese and normal-weight subjects and to determine kinetic changes induced by caloric restriction. DESIGN The cohort comprised 14 normal-weight women and 51 obese women who were followed over 2 y after Roux-en-Y gastric bypass. Multiplexed proteomics were used to simultaneously assay 27 cytokines and growth factors in serum. RESULTS Concentrations of interleukin (IL)-9, IL-1-receptor antagonist, IL-10, interferon-γ-inducible protein 10, macrophage inflammatory protein 1β, monocyte chemoattractant protein 1, IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), monokine induced by interferon-γ, and vascular endothelial growth factor were found to be elevated in obesity. IL-10 was further elevated in diabetic obese patients, whereas eotaxin was found to be higher only in diabetic subjects. After surgery, many factors showed a biphasic pattern of variation, decreasing sharply at month 3 before rising back to presurgical values at month 6; these changes closely tracked similar kinetic changes in calorie and carbohydrate intake. After 1 y, an overall reduction in cytokines accompanied the reduction in body mass index and an amelioration in metabolic status. CONCLUSIONS Obesity is associated with elevated circulating concentrations of a large panel of cytokines. Coordinated kinetic changes during weight loss suggest an early influence of calorie and carbohydrate intakes, whereas a longer-term reduction in corpulence might prevail in regulating circulating cytokine concentrations. This trial is registered at clincaltrials.gov as NCT00476658.

Association of Adipose Tissue and Liver Fibrosis With Tissue Stiffness in Morbid Obesity: Links With Diabetes and BMI Loss After Gastric Bypass

CONTEXT Liver and white adipose tissue (WAT) develop inflammation and fibrosis. OBJECTIVE The aim of the study was to evaluate the bioclinical relevance of WAT fibrosis in morbid obesity and diabetes and the relationships with tissue stiffness measured using a novel device. DESIGN AND SETTING Observational and longitudinal studies were conducted in a hospital nutrition department. PATIENTS Biopsies of liver and subcutaneous WAT (scWAT) and omental adipose tissue were collected from 404 obese bariatric surgery candidates, of whom 243 were clinically characterized before surgery and 3, 6, and 12 months after surgery. In 123 subjects, liver and scWAT stiffness was assessed noninvasively using vibration-controlled transient elastography (VCTE). INTERVENTIONS Bariatric surgery was performed for some patients. MAIN OUTCOME MEASURE Adipose tissue fibrosis and stiffness and their link to obesity phenotypes were measured. RESULTS scWAT fibrosis was positively associated with liver fibrosis (fibrosis score ≥2) (ϱ= 0.14; P = .01). VCTE-evaluated liver and scWAT stiffness was positively correlated with immunohistochemistry-determined liver (ϱ= 0.46; P = .0009) and scWAT fibrosis (ϱ= 0.48; P = .0001). VCTE-evaluated scWAT stiffness measures negatively associated with dual-energy x-ray absorptiometry-evaluated body fat mass (R = -0.25; P = .009) and were correlated with metabolic variables. Diabetic subjects showed increased scWAT stiffness. Participants less responsive to gastric bypass were older and more frequently diabetic, and they had increased body mass index, serum IL-6, and scWAT and liver fibrosis. Subjects with no diabetes and normal liver had higher fat mass and lower tissue fibrosis and stiffness. CONCLUSION scWAT stiffness was associated with tissue fibrosis, obesity, and diabetes-related traits. Noninvasive evaluation of scWAT stiffness might be useful in clinical practice.

Intima-media thickness in severe obesity: links with BMI and metabolic status but not with systemic or adipose tissue inflammation.

OBJECTIVE Obesity is associated with cardiovascular risk and a low-grade inflammatory state in both blood and adipose tissue (AT). Whether inflammation contributes to vascular alteration remains an open question. To test this hypothesis, we measured arterial intima-media thickness (IMT), which reflects subclinical atherosclerosis, in severely obese subjects and explored associations with systemic inflammation and AT inflammation. RESEARCH DESIGN AND METHODS IMT of the carotid artery (C-IMT) and IMT of the femoral artery (F-IMT) were measured in 132 nonobese (control) subjects (BMI 22.3 kg/m2; mean age 44.8 years) and 232 subjects who were severely obese without diabetes (OB/ND; n = 146; BMI 48.3 kg/m2; age 38.2 years) or severely obese with type 2 diabetes (OB/D; n = 86; BMI 47.0; age 49.4 years). In 57 OB/ND subjects, circulating soluble E-selectin, matrix metalloproteinase 9, myeloperoxidase, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, tissue plasminogen activator inhibitor 1, cystatin C, cathepsin S, and soluble CD14 were measured in serum. AT macrophages were quantified by CD68 immunochemistry. RESULTS Both C-IMT and F-IMT increased in OB/ND and OB/D patients. In OB/ND patients, age was the sole independent determinant of IMT. No significant association was found with circulating inflammation-related molecules, number of CD68+ cells, or the presence of crown-like structures in visceral or subcutaneous AT of OB/ND patients. CONCLUSIONS IMT increased with severe obesity but was not influenced by the degree of systemic inflammation or AT macrophage accumulation.

AdipoScan™ - A novel transient elastography based tool to assess subcutaneous adipose tissue shear wave speed in morbidly obese patients

Subcutaneous white adipose tissue (scWAT) in human obesity undergoes severe alterations such as fibrosis accumulation. Fibrosis in scWAT is related to metabolic alterations and to less efficiency in losing weight after bariatric surgery. There is currently no non-invasive tool to assess subcutaneous white adipose tissue (scWAT) characteristics. A novel device named AdipoScan™ based on vibration controlled transient elastography (VCTE™) was developed by Echosens so as to assess scWAT shear wave speed (SWS). In the present study, the prototype and how it has been adapted to scWAT SWS evaluation was first described. Repeatability was then assessed in terms of coefficient of variation (CV) with and without repositioning on tissue mimicking phantoms (~1% and 0%, respectively) and in vivo on 41 volunteers (14% and 7%, respectively). Then, scWAT SWS was measured in vivo on 73 morbidly obese patients candidate to bariatric surgery. scWAT SWS is significantly associated with tissue fibrosis, gender, body fat mass assessed by DXA, hypertension status, and biological parameters such as glycemia, lipid profile, hepatic parameters and adiponectin. Results suggest that scWAT evaluation before surgery can be useful in clinical practice to help phenotype obese patients and the stage of adipose tissue alterations.

Deficiency of FcϵR1 Increases Body Weight Gain but Improves Glucose Tolerance in Diet-Induced Obese Mice

Prior studies demonstrated increased plasma IgE in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcϵR1-deficient (Fcer1a(-/-)) mice and diet-induced obesity (DIO) mice demonstrated that FcϵR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue from Fcer1a(-/-) mice showed an increased expression of phospho-AKT, CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ, glucose transporter-4 (Glut4), and B-cell lymphoma 2 (Bcl2) but reduced uncoupling protein 1 (UCP1) and phosphorylated c-Jun N-terminal kinase (JNK) expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake but induces energy expenditure, adipocyte apoptosis, and white adipose tissue inflammation. In 3T3-L1 cells, IgE inhibited the expression of CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ, and preadipocyte adipogenesis and induced adipocyte apoptosis. IgE reduced the 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a(-/-) mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.

Metabolic Steatosis & Fibrosis: Review of the Non-Invasive Tools for Diagnosis and Screening

Hepatic steatosis affects 20% to 30% of the general adult population in affluent countries. Metabolic syndrome and its components—type 2 diabetes mellitus and central obesity— lead to the development of nonalcoholic fatty liver disease (NAFLD), in part due to insulin resistance, apoptosis and altered adipokine and cytokine pathways. Indeed, NAFLD is now considered the hepatic manifestation of metabolic syndrome. Globally, NAFLD is a common cause of chronic liver disease and, as the obesity epidemic continues, the prevalence of NAFLD is anticipated to increase. Non Alcoholic Fatty Disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), the latter characterized by steatosis plus necroinflammation. NASH can have different stages of fibrosis ranging from absent (stage F0) to cirrhosis (stage F4). Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Four new non-invasive methods received independent validation to assess NASH diagnosis (serologic tests) or to stage advanced fibrosis (blood tests, magnetic resonance elastography (MRE) and vibration controlled transient elastography (VCTE)). The chapter is organized as follows: section 2 describes natural history of NAFLD and NASH. The epidemiology is detailed section 3 and the risk factors in section 4. Than the limitations of liver biopsy are explained section 5; section 6 contains a description of non invasive tools clinically used or at the contrary new development not yet clinically evaluated. Advantages and limitations of these devices are detailed. Their applications in NAFLD diseases are described. Eventually, discussion and conclusion are drawn in section 6 and section 7, respectively.