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, 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: 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.
Background: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear. ...Objectives: We 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. Methods: Seventy-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. Results: POP content (17 dioxins/furans and 18 polychlorinated biphenyi 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 biphenyi body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index. Conclusions: POP content in adipose tissue and serum correlate with biological markers of obesityrelated dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Reduction of Macrophage Infiltration and Chemoattractant Gene Expression Changes in White Adipose Tissue of Morbidly Obese
Subjects After Surgery-Induced Weight Loss
Raffaella Cancello 1 ,
Corneliu ...Henegar 1 2 ,
Nathalie Viguerie 3 ,
Soraya Taleb 1 ,
Christine Poitou 1 ,
Christine Rouault 1 ,
Muriel Coupaye 1 ,
Veronique Pelloux 1 ,
Danielle Hugol 4 ,
Jean-Luc Bouillot 5 ,
Anne Bouloumié 3 6 ,
Giorgio Barbatelli 7 ,
Saverio Cinti 7 ,
Per-Arne Svensson 8 ,
Gregory S. Barsh 9 ,
Jean-Daniel Zucker 1 10 ,
Arnaud Basdevant 1 ,
Dominique Langin 3 and
Karine Clément 1
1 Inserm “Avenir”, Paris 6 University EA3502 and Human Research Center on Nutrition (CRNH), Hôtel Dieu Hospital, AP/HP, Paris,
France
2 SPIM “Santé publique et informatique médicale” laboratory, INSERM ERM202, Paris, France
3 INSERM UPS U586, Obesity Research Unit, Louis Bugnard Institute, Paul Sabatier University, Toulouse, France
4 Department of Anatomo-Pathology, Hôtel Dieu Hospital, Paris, France
5 Department of Surgery, Hôtel Dieu Hospital, Paris, France
6 Cardiovascular Physiology Department, J.-W. Goethe University, Frankfurt, Germany
7 Institute of Normal Human Morphology-Anatomy, School of Medicine, Polytechnic University of Marche, Ancona, Italy
8 Department of Internal Medicine, Research Centre for Endocrinology and Metabolism, Sahlgrenska Academy, Goteborg University,
Goteborg, Sweden
9 Department of Pediatrics and Genetics, Howard Hugues Medical Institute, Beckman Center, Stanford University School of Medicine,
Stanford, California
10 LIM & BIO, Paris-Nord University, Paris, France
Address correspondence and reprint requests to Karine Clément, MD, PhD, Department of Nutrition, Hôtel-Dieu Hospital, 1, Place
du Parvis Notre-Dame, 75004 Paris, France. E-mail: karine.clement{at}htd.ap-hop-paris.fr
Abstract
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 scWAT-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 < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in
macrophage attraction (monocyte chemotactic protein MCP-1, plasminogen activator urokinase receptor PLAUR, and colony-stimulating
factor CSF-3) and hypoxia (hypoxia-inducible factor-1α HIF-1α), expression of which increases in obesity and decreases
after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight
loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1α may play roles in the attraction
of macrophages in scWAT.
CRP, C-reactive protein
CSF, colony-stimulating factor
GO, Gene Ontology Consortium
FDR, false discovery rate
HIF-1α, hypoxia-inducible factor-1α
IL, interleukin
MCP, monocyte chemotactic protein
ORO, orosomucoid
PLAUR, plasminogen activator urokinase receptor
RTqPCR, real-time quantitative PCR
SAA, serum amyloid A
SAM, significance analysis of microarrays
scWAT, subcutaneous WAT
SVF, stroma vascular fraction
WAT, white adipose tissue
Footnotes
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 May 16, 2005.
Received January 17, 2005.
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.
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
ABSTRACT
Adipose tissue produces inflammation and immunity molecules suspected to be involved in obesity‐related complications. The pattern of expression and the nutritional regulation of these ...molecules in humans are poorly understood. We analyzed the gene expression profiles of subcutaneous white adipose tissue from 29 obese subjects during very low calorie diet (VLCD) using cDNA microarray and reverse transcription quantitative PCR. The patterns of expression were compared with that of 17 non‐obese subjects. We determined whether the regulated genes were expressed in adipocytes or stromavascular fraction cells. Gene expression profiling identified 100 inflammation‐related transcripts that are regulated in obese individuals when eating a 28 day VLCD but not a 2 day VLCD. Cluster analysis showed that the pattern of gene expression in obese subjects after 28 day VLCD was closer to the profile of lean subjects than to the pattern of obese subjects before VLCD. Weight loss improves the inflammatory profile of obese subjects through a decrease of proinflammatory factors and an increase of anti‐inflammatory molecules. The genes are expressed mostly in the stromavascular fraction of adipose tissue, which is shown to contain numerous macrophages. The beneficial effect of weight loss on obesity‐related complications may be associated with the modification of the inflammatory profile in adipose tissue.— Clément, K., Viguerie, N., Poitou, C., Carette, C., Pelloux, V., Curat, C. A., Sicard, A., Rome, S., Benis, A., Zucker, J.‐D., Vidal, H., Laville, M., Barsh, G. S., Basdevant, A., Stich, V., Cancello R., Langin, D. Weight loss regulates inflammation‐related genes in white adipose tissue of obese subjects. FASEB J. 18, 1657–1669 (2004)
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The prevalence of obesity is rising progressively, even among older age groups. By the year 2030–2035 over 20% of the adult US population and over 25% of the Europeans will be aged 65 years and ...older. The predicted prevalence of obesity in Americans, 60 years and older was 37% in 2010. The predicted prevalence of obesity in Europe in 2015 varies between 20 and 30% dependent on the model used. This means 20.9 million obese 60+ people in the USA in 2010 and 32 million obese elders in 2015 in the EU. Although cut-off values of BMI, waist circumference and percentages of fat mass have not been defined for the elderly (nor for the elderly of different ethnicity), it is clear from several meta-analyses that mortality and morbidity associated with overweight and obesity only increases at a BMI above 30 kg/m2. Thus, treatment should only be offered to patients who are obese rather than overweight and who also have functional impairments, metabolic complications or obesity-related diseases, that can benefit from weight loss. The weight loss therapy should aim to minimize muscle and bone loss but also vigilance as regards the development of sarcopenic obesity – a combination of an unhealthy excess of body fat with a detrimental loss of muscle and fat-free mass including bone – is important in the elderly, who are vulnerable to this outcome. Life-style intervention should be the first step and consists of a diet with a 500 kcal (2.1 MJ) energy deficit and an adequate intake of protein of high biological quality together with calcium and vitamin D, behavioural therapy and multi-component exercise. Multi-component exercise includes flexibility training, balance training, aerobic exercise and resistance training. The adherence rate in most studies is around 75%. Knowledge of constraints and modulators of physical inactivity should be of help to engage the elderly in physical activity. The role of pharmacotherapy and bariatric surgery in the elderly is largely unknown as in most studies people aged 65 years and older have been excluded.
Gastroesophageal reflux disease (GERD) is a common obesity-related co-morbidity that routinely is treated by continuous proton pump inhibitor (PPI) therapy. A number of concerns have been raised ...regarding the risk of de novo GERD or exacerbation of preexisting GERD after sleeve gastrectomy (SG).
To assess PPI use at 4 years after bariatric surgery.
French National Health Insurance.
Data were extracted from the French National Health Insurance database. All adult obese patients who had undergone gastric bypass (GBP) (n = 8250) or SG (n = 11,923) in 2011 in France were included. Patients were considered to be on continuous PPI therapy when PPIs were dispensed≥6 times per year. Logistic regression models were used to compute odds ratios for potential risk factors for PPI reimbursement 4 years after surgery.
Overall, continuous use of PPIs increased from baseline to 4 years after SG and GBP, from 10.9% to 26.5% (P<.001) and from 11.4% to 21.9% (P<.001), respectively. Among patients who underwent PPI therapy before surgery, those who had undergone SG were more likely to continue PPI therapy 4 years after surgery compared with those who underwent GBP (72.7% versus 59.2%; P<.001). In multivariate analyses, the major risk factors for persistent continuous PPI treatment 4 years after surgery were the following: SG (odds ratio OR = 1.87; 95% confidence interval CI 1.55-2.25), higher body mass index (OR 1.85; 95% CI 1.35-2.5), and preoperative antidepressant treatment (OR 1.89; 95% CI 1.56-2.29).
At a nationwide scale, continuous PPI treatment is used by 1 of 10 obese patients before bariatric surgery, but by 1 of 4 patients 4 years after surgery. SG compared with GBP, higher body mass index, and other coexisting conditions are the 3 major risk factors for medium-term continuous PPI therapy.
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