The EndoBarrier Gastrointestinal Liner is a feasible and safe noninvasive device with excellent short-term weight loss results. The device also has a significant positive effect on type 2 diabetes mellitus. Long-term randomized and sham studies for weight loss and treatment of diabetes are necessary to determine the role of the device in the treatment of morbid obesity.This study was registered at www.clinicaltrials.gov (registration number: NCT00830440).

OBJECTIVE:To study whether an increase of plasma leptin concentrations, as observed in the case of increased body weight, is associated with an inflammatory state. SUBJECTS: Sixty-three healthy subjects with body mass index (BMI) ranging from 20 to 61 kg=m 2 . MEASUREMENTS: Plasma concentrations of leptin, the inflammatory parameter soluble TNF-a receptors (TNFR55 and TNFR75), the acute phase proteins lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), a-acid glycoprotein (AGP), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1) and the anti-inflammatory soluble Interleukin-1 decoy receptor (sIL-1RII) were measured. RESULTS: As expected, BMI correlated significantly with leptin (r ¼ 0.823, P < 0.001), but also with all acute phase proteins, both soluble TNF receptors and PAI concentrations. After correction for BMI and sex, no significant correlation between leptin and the acute phase proteins was seen. Interestingly, however, leptin strongly correlated with both TNF receptors (r ¼ 0.523, P < 0.001 for TNFR55 and r ¼ 0.438, P < 0.001 for TNFR75). CONCLUSIONS: This study shows the development of a pro-inflammatory state with increasing body weight. The BMI independent relationship between leptin and both soluble TNF-receptors is consistent with a regulatory role for leptin in the inflammatory state in morbidly obese subjects.

BackgroundThe liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors.ResultsBy analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression.ConclusionsOur analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-860) contains supplementary material, which is available to authorized users.

IntroductionLPS is a constituent of the outer membrane of gramnegative bacteria and evokes an inflammatory response by activation of monocytes and endothelial cells. LPSinduced cellular responses are the net result of the interaction of LPS with various plasma components such as soluble CD14, LPS-binding protein (LBP) and membrane receptors such as membrane-bound CD14 and Toll-like receptors. This initiation of cellular responses is essential for the host defense against bacterial infections. However, if large amounts of endotoxin are present in the circulation, an excessive cellular response can be deleterious for the host, and, therefore, endotoxin-inactivating processes are of extreme importance.LPS is detoxified in the circulation by incorporation into lipoproteins (reviewed in ref. 1). Physiological levels of lipoproteins protect against endotoxicity in vitro and in vivo (2, 3). Early studies have demonstrated an interaction of LPS with HDL (4); albeit later, also VLDL and LDL were found to bind and inactivate LPS (5-7). Consistent with this, LDL, VLDL, chylomicrons, and HDL all have been observed to reduce the lethal effect of endotoxin in mice (8-10).Evidence for a physiological role for LBP in inflammation is supported by studies that demonstrate enhanced mortality and uncontrolled multiplication and spread of bacteria in LBP knockout mice compared with wild-type mice after intraperitoneal administration of bacteria (11). The results of these studies indicate that LBP is required to induce a rapid inflammatory response, which is essential for the resistance to bacteria. However, LBP has the paradoxical dual function of sensitizing the immune system to endotoxin and, on the other hand, enhancing detoxification of endotoxin. LBP catalyzes the transfer of LPS into lipoproteins, thereby enhancing LPS detoxification (12). Likewise, LBP catalyzes the lipoprotein neutralization of lipoteichoic acid, a component of the cell membrane of gram-positive bacteria (13). Lamping et al. demonstrated in a murine model that high levels of LBP in the circulation, as seen during an acute-phase response, inhibit LPS effects and prevent mortality induced by endotoxemia (14). The latter observation strongly supports a physiological role for LBP-dependent detoxification of LPS in the host defense.Endotoxemia induces an acute-phase response characterized by multiple physiological adaptations. This response appears to play a role in host defense mechanisms, although its physiological relevance needs further elucidation. One aspect of the acute-phase response is a dramatic rise in circulating levels of LBP LPS-binding protein (LBP) and serum lipoproteins cooperate in reducing the toxic properties of LPS.In the present study, we demonstrate that LBP circulates in association with LDL and VLDL in healthy persons. ApoB was found to account at least in part for the interaction of LBP with LDL and VLDL. Although LBP interacted with purified apoA-I in vitro, no association of LBP with apoA-I or HDL was found in serum. Consistent with th...

Obesity is demonstrated to be associated with an enhanced inflammatory state, which is suggested to be a cause for the development of obesity-related morbidity. It was hypothesized that a decrease in body weight in morbid obese subjects would lead to a reduction of the inflammatory state in these subjects.Weight loss was achieved by gastric restrictive surgery in 27 morbidly obese patients. Preoperative as well as 3-, 6-, 12-, and 24-month postoperative plasma concentrations of inflammatory mediators macrophage inhibitory factor, plasminogen activator inhibitor-1, lipopolysaccharide binding protein, ␣-1 acid glycoprotein, C-reactive protein, soluble TNF␣ receptors 55 and 75, and leptin were measured.Macrophage inhibitory factor levels remained low normal for 6 months, during weight loss, after which they significantly increased to normal levels at 24 months postoperatively. The other inflammatory mediators remained elevated up to minimally 3 months postoperatively; thereafter they decreased significantly. Both TNF␣ receptors remained elevated up to at least 12 months postoperatively to decrease significantly at 2 yr postoperatively.This study demonstrates that during weight loss, after gastric restrictive surgery, inflammatory mediators remain elevated for at least 3 months postoperatively, suggesting initially an ongoing inflammatory state. However, 2 yr after surgery, the inflammatory mediators reach near normal values.These findings may be an explanation for the reduced comorbidity seen in morbidly obese patients after gastric restrictive surgery. (J Clin Endocrinol Metab 89: [4062][4063][4064][4065][4066][4067][4068] 2004)