Co-expressed immune and metabolic genes in visceral and subcutaneous adipose tissue from severely obese individuals are associated with plasma HDL and glucose levels: a microarray study

<p>Abstract</p> <p>Background</p> <p>Excessive accumulation of body fat, in particular in the visceral fat depot, is a major risk factor to develop a variety of diseases such as type 2 diabetes. The mechanisms underlying the increased risk of obese individuals to develop co-morbid diseases are largely unclear.</p> <p>We aimed to identify genes expressed in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) that are related to blood parameters involved in obesity co-morbidity, such as plasma lipid and glucose levels, and to compare gene expression between the fat depots.</p> <p>Methods</p> <p>Whole-transcriptome SAT and VAT gene expression levels were determined in 75 individuals with a BMI >35 kg/m². Modules of co-expressed genes likely to be functionally related were identified and correlated with BMI, plasma levels of glucose, insulin, HbA_1c, triglycerides, non-esterified fatty acids, ALAT, ASAT, C-reactive protein, and LDL- and HDL cholesterol.</p> <p>Results</p> <p>Of the approximately 70 modules identified in SAT and VAT, three SAT modules were inversely associated with plasma HDL-cholesterol levels, and a fourth module was inversely associated with both plasma glucose and plasma triglyceride levels (p < 5.33 × 10^-5). These modules were markedly enriched in immune and metabolic genes. In VAT, one module was associated with both BMI and insulin, and another with plasma glucose (p < 4.64 × 10^-5). This module was also enriched in inflammatory genes and showed a marked overlap in gene content with the SAT modules related to HDL. Several genes differentially expressed in SAT and VAT were identified.</p> <p>Conclusions</p> <p>In obese subjects, groups of co-expressed genes were identified that correlated with lipid and glucose metabolism parameters; they were enriched with immune genes. A number of genes were identified of which the expression in SAT correlated with plasma HDL cholesterol, while their expression in VAT correlated with plasma glucose. This underlines both the singular importance of these genes for lipid and glucose metabolism and the specific roles of these two fat depots in this respect.</p

An Update on Less Invasive and Endoscopic Techniques Mimicking the Effect of Bariatric Surgery

Obesity (BMI 30–35 kg/m2) and its associated disorders such as type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease have reached pandemic proportions worldwide. For the morbidly obese population (BMI 35–50 kg/m2), bariatric surgery has proven to be the most effective treatment to achieve significant and sustained weight loss, with concomitant positive effects on the metabolic syndrome. However, only a minor percentage of eligible candidates are treated by means of bariatric surgery. In addition, the expanding obesity epidemic consists mostly of relatively less obese patients who are not (yet) eligible for bariatric surgery. Hence, less invasive techniques and devices are rapidly being developed. These novel entities mimic several aspects of bariatric surgery either by gastric restriction (gastric balloons, gastric plication), by influencing gastric function (gastric botulinum injections, gastric pacing, and vagal nerve stimulation), or by partial exclusion of the small intestine (duodenal-jejunal sleeve). In the last decade, several novel less invasive techniques have been introduced and some have been abandoned again. The aim of this paper is to discuss the safety, efficacy, complications, reversibility, and long-term results of these latest developments in the treatment of obesity

TP53 Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma

Objectives: Although TP53 mutations in head and neck squamous cell carcinoma (HNSCC) have been extensively studied, their association with the different subsites in the head and neck region has never been described. Methods: Sanger sequence analysis evaluating exons 4-9 in the TP53 gene was performed on 116 HNSCC patients. The exon location, exact codon and corresponding substitution in relation to the anatomical site (subsite) of the HNSCC were evaluated. Results: We found nonsynonymous TP53 mutations in 70% (81/116) of the patients. In oral cavity carcinomas, most mutations occurred in exon 7 (37%). In oropharyngeal and laryngeal tumors, mutations were mainly found in exons 6 and 7. The most common mutation was located in codon 220, and all of these were an Y220C mutation. Five out of nine (56%) Y220C mutations occurred in oropharyngeal tumors. Additionally, 22% of all mutations observed in oropharyngeal squamous cell carcinoma (OPSCC) consisted of Y220C mutations. Conclusion: In this study, the subsite-related distribution of TP53 mutations underlines the biological diversity between tumors arising from different anatomical regions in the head and neck region. Moreover, the Y220C mutation was by far the most prevalent TP53 mutation in HNSCC and a relative hotspot mutation in the oropharynx. (C) 2015 S. Karger AG, Base

Endoscopic Duodenal-Jejunal Bypass Liner Rapidly Improves Type 2 Diabetes

Background Bariatric procedures excluding the proximal small intestine improve glycemic control in type 2 diabetes within days. To gain insight into the mediators involved, we investigated factors regulating glucose homeostasis in patients with type 2 diabetes treated with the novel endoscopic duodenal-jejunal bypass liner (DJBL). Methods Seventeen obese patients (BMI 30-50 kg/m(2)) with type 2 diabetes received the DJBL for 24 weeks. Body weight and type 2 diabetes parameters, including HbA(1c) and plasma levels of glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, were analyzed after a standard meal before, during, and 1 week after DJBL treatment. Results At 24 weeks after implantation, patients had lost 12.7 +/- 1.3 kg (p &lt;0.01), while HbA(1c) had improved from 8.4 +/- 0.2 to 7.0 +/- 0.2 % (p &lt;0.01). Both fasting glucose levels and the postprandial glucose response were decreased at 1 week after implantation and remained decreased at 24 weeks (baseline vs. week 1 vs. week 24: 11.6 +/- 0.5 vs. 9.0 +/- 0.5 vs. 8.6 +/- 0.5 mmol/L and 1,999 +/- 85 vs. 1,536 +/- 51 vs. 1,538 +/- 72 mmol/L/min, both p &lt;0.01). In parallel, the glucagon response decreased (23,762 +/- 4,732 vs. 15,989 +/- 3,193 vs. 13,1207 +/- 1,946 pg/mL/min, p &lt;0.05) and the GLP-1 response increased (4,440 +/- 249 vs. 6,407 +/- 480 vs. 6,008 +/- 429 pmol/L/min, p &lt;0.01). The GIP response was decreased at week 24 (baseline-115,272 +/- 10,971 vs. week 24-88,499 +/- 10,971 pg/mL/min, p &lt;0.05). Insulin levels did not change significantly. Glycemic control was still improved 1 week after explantation. Conclusions The data indicate DJBL to be a promising treatment for obesity and type 2 diabetes, causing rapid improvement of glycemic control paralleled by changes in gut hormones.</p

Alternative pathway related factors in NASH.

<p>A) Hepatic properdin protein levels were not significantly different between subjects with a healthy liver and subjects with NASH (p = 0.92). B) Representative images of immunofluorescent stainings for properdin (green) and myeloperoxidase (MPO, red), showing pronounced extracellular accumulation of properdin in areas where neutrophils surround steatotic hepatocytes in subjects with NASH (100× magnification), whereas control subjects with healthy livers display no or little properdin accumulation and neutrophil infiltration (100× magnification). C) Quantitative analysis of immunofluorescent staining for MPO+ cells (***p<0.001) and properdin+/MPO+ cells (***p<0.001) in healthy livers and livers from subjects with NASH. D) Hepatic factor B mRNA expression was comparable in subjects with healthy livers and subjects with NASH (p = 0.26). E) Similar mRNA expression of factor D in the study groups (p = 0.29).</p

Association between properdin, DAF, and C3c with hepatic steatosis and inflammation.

<p>A) C3c levels in the liver were not different (p = 0.27) between subjects with grade 2 steatosis (N = 5) and subjects with grade 3 steatosis (N = 7). B) Levels of hepatic properdin were not related to the grade of steatosis (p = 0.27). C) Progressively increasing levels of hepatic C3c with higher lobular inflammation scores (**p<0.01). D) Hepatic C3 activation (C3c/native C3 ratio) was increased in subjects with highest lobular inflammation scores (**p<0.01). E) Gradually increasing hepatic properdin protein concentrations in subjects with higher lobular inflammation scores (*p<0.05). F) No correlation was observed between hepatic DAF protein levels and NAS score (r_s = 0.30; p = 0.34). G) Hepatic C3c protein levels were significantly correlated with NAS score in patients with NASH (r_s = 0.63; *p<0.05). H) A similar, but not significant correlation was observed between the C3c/native C3 activation ratio and NAS score (r_s = 0.51; p = 0.09). I) Hepatic Properdin protein levels did not correlated with NAS score (r_s = 0.42; p = 0.17).</p

Alterations in regulators of the alternative pathway in human NASH.

<p>A) Reduced factor H mRNA expression in the liver of subjects with NASH compared to subjects with healthy livers (*p<0.05). B) Semi-quantitative analysis of hepatic factor H protein levels (p = 0.08). C) Correlation between hepatic factor H and hepatic properdin protein levels in subjects with NASH (r_s = 0.56; p = 0.08). D) Hepatic DAF mRNA expression in patients with NASH compared to controls (p = 0.22). E) The increase in hepatic DAF protein levels in subjects with NASH was not statistically significant (p = 0.28). F) However, there was a significant correlation between hepatic DAF protein levels and the activation ratio of C3c/native C3 in subjects with NASH (r_s = 0.73; **p<0.01).</p