Fibrosis is increasingly appreciated as a major player in adipose tissue dysfunction. In rapidly expanding adipose tissue, pervasive hypoxia leads to an induction of HIF1α that in turn leads to a potent pro-fibrotic transcriptional program. The pathophysiological impact of adipose tissue fibrosis is likely to play an equally important role on systemic metabolic alterations as fibrotic conditions play in the liver, heart and kidney. Here, we discuss recent advances in our understanding of the genesis, modulation and systemic impact of excessive extracellular matrix (ECM) accumulation in adipose tissue of both rodents and humans and the ensuing impact on metabolic dysfunction.

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 1 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 (j 5 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.

OBJECTIVEFibrosis is a newly appreciated hallmark of the pathological alteration of human white adipose tissue (WAT). We investigated the composition of subcutaneous (scWAT) and omental WAT (oWAT) fibrosis in obesity and its relationship with metabolic alterations and surgery-induced weight loss.RESEARCH DESIGN AND METHODSSurgical biopsies for scWAT and oWAT were obtained in 65 obese (BMI 48.2 ± 0.8 kg/m2) and 9 lean subjects (BMI 22.8 ± 0.7 kg/m2). Obese subjects who were candidates for bariatric surgery were clinically characterized before, 3, 6, and 12 months after surgery, including fat mass evaluation by dual energy X-ray absorptiometry. WAT fibrosis was quantified and characterized using quantitative PCR, microscopic observation, and immunohistochemistry.RESULTSFibrosis amount, distribution and collagen types (I, III, and VI) present distinct characteristics in lean and obese subjects and with WAT depots localization (subcutaneous or omental). Obese subjects had more total fibrosis in oWAT and had more pericellular fibrosis around adipocytes than lean subjects in both depots. Macrophages and mastocytes were highly represented in fibrotic bundles in oWAT, whereas scWAT was more frequently characterized by hypocellular fibrosis. The oWAT fibrosis negatively correlated with omental adipocyte diameters (R = −0.30, P = 0.02), and with triglyceride levels (R = −0.42, P < 0.01), and positively with apoA1 (R = 0.25, P = 0.05). Importantly, scWAT fibrosis correlated negatively with fat mass loss measured at the three time points after surgery.CONCLUSIONSOur data suggest differential clinical consequences of fibrosis in human WAT. In oWAT, fibrosis could contribute to limit adipocyte hypertrophy and is associated with a better lipid profile, whereas scWAT fibrosis may hamper fat mass loss induced by surgery.

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 ␥-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. Diabetes 55: 1554 -1561, 2006

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.

Context: Chemerin is a new adipokine involved in in vitro adipogenesis and insulin resistance and associates with body mass index (BMI) in vivo.Objective: We investigated the role of chemerin in morbid obesity, associated metabolic diseases (insulin resistance, hepatic diseases), and postsurgery-induced weight loss. Setting:This was a prospective study performed at a university hospital.Subjects: Subjects included 60 obese female patients (BMI 50.0 Ϯ 1.0 kg/m Ϫ2 ) being candidates for gastric bypass.Study Design: Patients were examined before and 3, 6, and 12 months after surgery. In 27 patients, chemerin was measured after 2 yr.Main Outcome: Outcomes included chemerin, anthropometric parameters, homeostasis model assessment for insulin resistance index (HOMA-IR), cholesterol, high-density lipoprotein, triglycerides, C-reactive protein, adipokines at all time points; and liver histology and macrophage content in fat at baseline. Results:Chemerin was substantially elevated in obese patients compared with nonobese persons (353.8 Ϯ 18.0 vs. 191 Ϯ 14 ng/ml, P Ͻ 0.001). Preoperatively, chemerin concentrations correlated positively with BMI, C-reactive protein, IL-6, HOMA-IR, and the amount of omental macrophages and negatively with high-density lipoprotein levels. Baseline chemerin was elevated in patients with a significant activity score for nonalcoholic fatty liver disease, portal inflammation, fibrosis, and fibroinflammation. After surgery, chemerin decreased significantly to 253.0 Ϯ 14.9 ng/ml after 1 yr and pursued its decrease in patients studied for 2 yr. After surgery, chemerin concentrations positively correlated with triglycerides. The strong decrease of chemerin in the 3 months after surgery was associated with the decrease in HOMA-IR and blood glucose. Conclusions:Chemerin concentrations are elevated in morbidly obese patients and correlated with insulin resistance and markers of liver pathology. Chemerin plasma concentrations decreased after bariatric surgery. This study suggests that chemerin might mediate metabolic alterations in obesity, drastically improving after gastric bypass. O besity is one of the most serious health hazards and frequently accompanied by metabolic disturbances (1). Increased adipose tissue mass, especially in the visceral compartment, is characterized by altered metabolic and endocrine function leading to an increased secretion of proinflammatory adipokines. These secreted molecules may be factors underlying the association between increased body fat and metabolic complications such as insulin resistance in peripheral organs or ectopic fat accumulation. Chemerin is a recently described adipokine

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.

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.