Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and being overweight is a significant risk factor. The aim was to build an algorithm along with a scoring system for histopathologic ...classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients. A cohort of 679 obese patients undergoing liver biopsy at the time of bariatric surgery was studied. An algorithm for segregating lesions into normal liver, NAFLD, or nonalcoholic steatohepatitis (NASH) was built based on semiquantitative evaluation of steatosis, hepatocellular ballooning, and lobular inflammation. For each case, the SAF score was created including the semiquantitative scoring of steatosis (S), activity (A), and fibrosis (F). Based on the algorithm, 230 obese patients (34%) were categorized as NASH, 291 (43%) as NAFLD without NASH, and 158 (23%) as not NAFLD. The activity score (ballooning + lobular inflammation) enabled discriminating NASH because all patients with NASH had A ≥ 2, whereas no patients with A < 2 had NASH. This score was closely correlated with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.0001, analysis of variance ANOVA). Comparison of transaminase levels between patients with normal liver and pure steatosis did not reveal significant differences, thus lending support to the proposal not to include steatosis in the activity score but to report it separately in the SAF score. In the validation series, the interobserver agreement for the diagnosis of NASH was excellent (κ = 0.80) between liver pathologists. There was no discrepancy between the initial diagnosis and the diagnosis proposed using the algorithm. Conclusion: We propose a simple but robust algorithm for categorizing liver lesions in NAFLD patients. Because liver lesions in obese patients may display a continuous spectrum of histologic lesions, we suggest describing liver lesions using the SAF score. (HEPATOLOGY 2012;56:1751–1759)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background & Aims Morbid obesity is frequently associated with low grade systemic inflammation, increased macrophage accumulation in adipose tissue (AT), obstructive sleep apnea (OSA), and ...nonalcoholic fatty liver disease (NAFLD). It has been suggested that chronic intermittent hypoxia (CIH) resulting from OSA could be an independent factor for early stage of NAFLD in addition to other well-recognized factors (dyslipidemia or insulin resistance). Moreover, macrophage accumulation in AT is associated with local hypoxia in fat tissue. We hypothesized that the association between CIH and morbid obesity could exert additional specific deleterious effects both in the liver and adipose tissues. Methods One hundred and one morbidly obese subjects were prospectively recruited and underwent bariatric surgery during which a liver needle biopsy as well as surgical subcutaneous and omental AT biopsies were obtained. Oxygen desaturation index (ODI) quantified the severity of nocturnal CIH. Results Histopathologic analysis of liver biopsies demonstrated that NAFLD lesions (ballooning of hepatocytes, lobular inflammation), NAFLD activity score (NAS), and fibrosis were significantly more severe in patients with the highest ODI tertile ( p values ⩽0.001 for all hepatic lesions). In multivariate analysis, after adjustment for age, obesity, and insulin resistance status, CIH remained independently associated with hepatic fibrosis, fibroinflammation, and NAS. By contrast, no association was found between CIH, macrophage accumulation, and adipocytes size in both subcutaneous and omental adipose tissue. Conclusions In morbidly obese patients, CIH was strongly associated with more severe liver injuries but did not worsen obesity induced macrophage accumulation in adipose tissue depots.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Context:
Extracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored.
Objective:
The ...objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements.
Design, Setting, Patients, and Interventions:
A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS.
Main Outcome Measures:
scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls.
Results:
Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163+ cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase LOX, LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation.
Conclusions:
After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss.
Context: Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this ...is accompanied by phenotypic changes is unknown.
Objective: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity.
Design/Setting: We performed a single-center prospective study.
Participants/Interventions: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 ± 8.6 yr; body mass index 43.8 ± 3.4 kg/m2). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 ± 3.5 yr; body mass index 22.5 ± 0.75 kg/m2). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry.
Main Outcomes: The number of CD40+ macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163+ and CD206+ macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40+ to CD206+ macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P < 0.001) due to a concomitant decrease of CD40+ and increase of CD206+ macrophages counts.
Conclusion: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.
Immunohistochemistry analyses suggest that gastric surgery switches the activation state of adipose tissue macrophages towards a M2-oriented, less pro-inflammatory phenotype in morbidly obese subjects.
Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue ...(WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.
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•Mast cells in WAT from lean humans and mice are leptin deficient•Reconstitution of leptin-deficient mast cells mitigates obesity and diabetes in mice•Leptin-deficient mast cells promote M2 macrophage polarization•Leptin-deficient mast cells slant anti-inflammatory signaling in response to leptin
Proinflammatory mast cells play detrimental roles in obesity and diabetes. Zhou et al. show that mast cells in white adipose tissues from lean humans and mice are leptin deficient and polarize macrophages toward anti-inflammatory M2 phenotype. Adoptive transfer of leptin-deficient mast cells mitigates obesity and diabetes in obese mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Epidemiological studies emphasize the possible role of persistent organic pollutants (POPs) in obesity and the metabolic syndrome. These pollutants are stored in adipose tissue (AT). ...Objectives: Our aim was to study the effects of POPs on human adipose cells and rodent AT. Methods: Using human multipotent adipose-derived stem cells, we carried out large-scale gene expression analysis to identify the major pathways modified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl (PCB) congener 126 (PCB-126), and PCB-153 and to evaluate their toxic effects. The effects of TCDD on gene expression and AT histology were also assessed in mice. Results: The most significantly regulated genes in both precursor cells and adipocytes were those involved in the inflammatory/immune response, cancer, and metabolism pathways. Interestingly, the fold induction and the number of modulated genes were higher in precursors than in adipocytes, suggesting that the former could be more sensitive to the effect of pollutants. When cells were treated with combinations of pollutants, the effects of the AhR ligands TCDD and PCB-126 were dominant compared with those of the non-dioxin-like PCB-153. The effects of AhR ligands were reduced by the AhR antagonist α-naphthoflavone. The regulation of inflammatory pathway was observed in wild-type AT but not in AhR-knockout mice. Conclusions: Both in vitro and in vivo studies showed that adipose cells were targets of AhR ligands and suggest that inflammation is one of the main regulated pathways. These observations suggest a possible contribution of pollutants to low-grade AT inflammation that accompanies the pathogenesis of metabolic diseases.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Abstract
Context:
Bariatric surgery (BS) induces major and sustainable weight loss in many patients. Factors predicting poor weight-loss response (PR) need to be identified to improve patient care. ...Quantification of subcutaneous adipose tissue (scAT) fibrosis is negatively associated with post-BS weight loss, but whether it could constitute a predictor applicable in clinical routine remains to be demonstrated.
Objective:
To create a semiquantitative score evaluating scAT fibrosis and test its predictive value on weight-loss response after Roux-en-Y gastric bypass (RYGB).
Methods:
We created a fibrosis score of adipose tissue (FAT score) integrating perilobular and pericellular fibrosis. Using this score, we characterized 183 perioperative scAT biopsy specimens from severely obese patients who underwent RYGB (n = 85 from a training cohort; n = 98 from a confirmation cohort). PR to RYGB was defined as <28% of total weight loss at 1 year (lowest tertile). The link between FAT score and PR was tested in univariate and multivariate models.
Results:
FAT score was directly associated with increasing scAT fibrosis measured by a standard quantification method (P for trend <0.001). FAT score interobserver agreement was good (κ = 0.76). FAT score ≥2 was significantly associated with PR. The association remained significant after adjustment for age, diabetes status, hypertension, percent fat mass, and interleukin-6 level (adjusted odds ratio, 3.6; 95% confidence interval, 1.8 to 7.2; P = 0.003).
Conclusion:
The FAT score is a new, simple, semiquantitative evaluation of human scAT fibrosis that may help identify patients with a potential limited weight-loss response to RYGB.
A simple, reproducible semiquantitative score of adipose tissue fibrosis was created. It is associated with poorer weight-loss response to gastric bypass independently of other known predictors.
Increased Infiltration of Macrophages in Omental Adipose Tissue Is Associated With Marked Hepatic Lesions in Morbid Human
Obesity
Raffaella Cancello 1 2 3 ,
Joan Tordjman 1 2 3 ,
Christine Poitou 1 2 ...3 ,
Gaël Guilhem 1 2 3 ,
Jean Luc Bouillot 4 ,
Danielle Hugol 5 ,
Christiane Coussieu 6 ,
Arnaud Basdevant 1 2 3 ,
Avner Bar Hen 7 ,
Pierre Bedossa 8 9 ,
Michèle Guerre-Millo 1 2 3 and
Karine Clément 1 2 3
1 Institut National de la Santé et de la Recherche Médicale (INSERM), U755 Nutriomique, Paris, France
2 Pierre and Marie Curie-Paris 6 University, Faculty of Medicine, Les Cordeliers, IFR58, Paris, France
3 Nutrition Department, AP-HP, Hôtel-Dieu Hospital, Paris, France
4 Surgery Department, AP-HP, Hôtel Dieu Hospital, Paris, France
5 Anatomo-Pathology Department, AP-HP, Hôtel Dieu Hospital, Paris, France
6 Biochemistry Department, AP-HP, Hôtel Dieu Hospital, Paris, France
7 LIM and BIO, Paris 13 University, Bobigny, France
8 Pathology Department, AP-HP Beaujon Hospital, Clichy France
9 National Center for Scientific Research, Unité Mixte de Recherche 149, Paris, France
Address correspondence and reprint requests to Prof. Karine Clément, INSERM, U755 Nutriomique, Service de Nutrition, Hôtel-Dieu,
1 Place du Parvis Notre-Dame, 75004 Paris, France. E-mail: karine.clement{at}htd.ap-hop-paris.fr
Abstract
In human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to
the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is
associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were
collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 ± 0.93 kg/m 2 ). The number of HAM56+ macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters
and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT
( P < 0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative
insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and γ-glutamyltranspeptidase. We propose
an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental
WAT was associated with hepatic fibroinflammatory lesions ( P = 0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macrophages.
These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic
fibroinflammatory lesions in obese patients.
AST, aspartate aminotransferase
γGT, γ-glutamyltranspeptidase
NAFLD, nonalcoholic fatty liver disease
QUICKI, quantitative insulin sensitivity check index
TBS-TC, Tris-buffered saline/Tween 20/casein 0.02 mol/l solution
TNF, tumor necrosis factor
WAT, white adipose tissue
Footnotes
R.C. and J.T. contributed equally to this work.
DOI: 10.2337/db06-0133
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 2, 2006.
Received January 31, 2006.
DIABETES
Investigations performed in mice and humans have acknowledged obesity as a low-grade 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.
Here, we analyzed the transcriptomic signature of the subcutaneous WAT in obese human subjects, in stable weight conditions and after weight loss following bariatric surgery. An original integrative functional genomics approach was applied to quantify relations between relevant structural and functional themes annotating differentially expressed genes in order to construct a comprehensive map of transcriptional interactions defining the obese WAT. These analyses highlighted a significant up-regulation of genes and biological themes related to extracellular matrix (ECM) constituents, including members of the integrin family, and suggested that these elements could play a major mediating role in a chain of interactions that connect local inflammatory phenomena to the alteration of WAT metabolic functions in obese subjects. Tissue and cellular investigations, driven by the analysis of transcriptional interactions, revealed an increased amount of interstitial fibrosis in obese WAT, associated with an infiltration of different types of inflammatory cells, and suggest that phenotypic alterations of human pre-adipocytes, induced by a pro-inflammatory environment, may lead to an excessive synthesis of ECM components.
This study opens new perspectives in understanding the biology of human WAT and its pathologic changes indicative of tissue deterioration associated with the development of obesity.
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