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Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC) is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h) and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of “healthy” and “diseased” states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity. [ABSTRACT FROM AUTHOR]

Background Infiltration of white adipose tissue ( WAT) by inflammatory cells in obesity is considered to be a key event in the development of insulin resistance. Recently, mast cells ( MCs) have been identified as new players in the pathogenesis of obesity. We aimed to investigate the relationship between MCs and various inflammatory markers in serum and WAT and to determine the role of MCs in the aetiology of insulin resistance. Materials and methods Gene expression was measured in WAT from 20 morbidly obese patients and 20 nonobese control subjects. Homoeostasis Model of Assessment-Insulin Resistance ( HOMA- IR) was used to estimate insulin sensitivity. In addition, wild-type and mast cell-deficient mice were fed a high-fat or low-fat diet to study mast cell influence on inflammatory cell polarization in WAT and overall metabolic changes. Results WAT levels of MC-specific TPSb2 transcript were increased in obesity and significantly positively correlated with TNF, CCL2, CCL5 and CD68 gene expression levels in our study subjects after adjustment for sex, age and BMI. Accordingly, MC deficiency abrogated increase in expression of pro-inflammatory M1 macrophage marker genes in mouse WAT upon high-fat diet feeding. However, MCs accumulated in obese human WAT independent of insulin resistance and systemic changes in inflammatory mediators. Conclusions Our results suggest that MCs contribute to the local pro-inflammatory state within WAT in obesity but do not play a primary role in causing insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Cytokines and chemokines in the tumor microenvironment drive metastatic development and their serum levels might mirror the ongoing inflammatory reaction at the tumor site. Novel highly sensitive tools are needed to identify colorectal cancer patients at high risk of recurrence that should be more closely monitored during post-surgical follow up. Here we study whether circulating inflammatory markers might be used to predict recurrence in CRC patients. Methods: Circulating levels of the inflammatory cytokines IL-1, IL-6, IL-10, TNFalpha, CCL2, CXCL8, VEGF and the acute phase protein Pentraxin-3 were measured by ELISA in preoperative serum samples prospectively collected from a cohort of sixty-nine patients undergoing surgical resection for stage 0–IV CRC and associated with post-operative disease recurrence. Results: Cox multivariate analysis showed that combined high levels (≥ROC cut off-value) of CXCL8, VEGF and Pentraxin3 were associated with increased risk of disease recurrence [HR: 14.28; 95%CI: (3.13–65.1)] independently of TNM staging. Kaplan-Meier analysis showed that CXCL8, VEGF and Pentraxin3 levels were significantly associated with worse survival (P<0.001). Conclusions: Circulating inflammatory mediators efficiently predicted postoperative recurrence after CRC surgery. Therefore, this study suggest that their validation in large-scale clinical trials may help in tailoring CRC post-surgical management. [ABSTRACT FROM AUTHOR]

Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures. [ABSTRACT FROM AUTHOR]

The article presents ten simple rules for a successful cross-disciplinary collaboration. Topics discussed include research in experimental biology, need of multidisciplinary collaborations, need to recognize the publication culture in the life sciences and in experimental biology, and publication of information technology research in peer-reviewed conference proceedings instead of journals.

Background: Dyslipidemia, a major risk factor for cardiovascular disease is a common finding in patients with type 2 diabetes and among women with gestational diabetes. Elevated levels of lipoprotein(a) [Lp(a)] are linked to increased risk of cardiovascular disease. However, its relationship with insulin resistance, type 2 diabetes and gestational diabetes is controversial and unproven. Here we aimed to clarify whether Lp(a) levels are associated with insulin sensitivity in pregnancy. Methods: Sixty-four women with gestational diabetes and 165 with normal glucose tolerance were enrolled in the study. Fasting Lp(a) serum levels were measured in all women at 24-28 weeks of gestation. Results: In pregnancy, there was no significant difference in serum Lp(a) concentrations between the two groups. Its level did not correlate with markers of insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S%), pancreatic beta-cell function (HOMA-B%) and insulin sensitivity in dynamic conditions (OGIS). In addition, fasting glucose and insulin levels and those throughout an oral glucose tolerance test were independent of Lp(a) concentrations in our study group. Conclusions: Lp(a) levels in pregnant women do not differ with respect to the presence or absence of gestational diabetes. Although influenced by some components of the lipid profile, such as triglycerides and HDL-C, insulin resistance in pregnancy is not affected by Lp(a). [ABSTRACT FROM AUTHOR]

Antigen presenting cells present processed peptides via their major histocompatibility (MH) complex to the T cell receptors (TRs) of T cells. If a peptide is immunogenic, a signaling cascade can be triggered within the T cell. However, the binding of different peptides and/or different TRs to MH is also known to influence the spatial arrangement of the MH α-helices which could itself be an additional level of T cell regulation. In this study, we introduce a new methodology based on differential geometric parameters to describe MH deformations in a detailed and comparable way. For this purpose, we represent MH α-helices by curves. On the basis of these curves, we calculate in a first step the curvature and torsion to describe each α-helix independently. In a second step, we calculate the distribution parameter and the conical curvature of the ruled surface to describe the relative orientation of the two α-helices. On the basis of four different test sets, we show how these differential geometric parameters can be used to describe changes in the spatial arrangement of the MH α-helices for different biological challenges. In the first test set, we illustrate on the basis of all available crystal structures for (TR)/pMH complexes how the binding of TRs influences the MH helices. In the second test set, we show a cross evaluation of different MH alleles with the same peptide and the same MH allele with different peptides. In the third test set, we present the spatial effects of different TRs on the same peptide/MH complex. In the fourth test set, we illustrate how a severe conformational change in an α-helix can be described quantitatively. Taken together, we provide a novel structural methodology to numerically describe subtle and severe alterations in MH α-helices for a broad range of applications. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Pentraxin 3 ( PTX3) is a cytokine-inducible molecule expressed in different tissues, the levels of which increase in a response to a variety of inflammatory conditions. Recently, it has been linked to the serum glucose levels and some comorbidities in type 2 diabetes. Materials and methods Here, we aimed to investigate the role of PTX3 in gestational diabetes mellitus ( GDM), which is considered a forerunner of type 2 diabetes. Fasting PTX3 serum levels were measured in 90 women [45 GDM, 45 normal glucose tolerance ( NGT)] during pregnancy. In addition, PTX3 was measured during a 2 h, 75 g oral glucose tolerance test ( OGTT) in 20 women (10 GDM, 10 NGT) at 24-28 weeks of gestation and in 16 of them after delivery (10 GDM, 6 NGT). Results A continuous increase in PTX3 levels was observed during the OGTT and reached in the GDM group a significant difference after 120 min compared with baseline ( P < 0·05). Additionally, a rise in the PTX3 concentration was significantly higher in the GDM- compared with the NGT group, 120 min after glucose challenge ( P < 0·01). During pregnancy, serum glucose and C-peptide were positively correlated with the PTX3 levels in the whole study group, whereas a negative association was found with the insulin sensitivity parameters QUICKI and OGIS. Conclusions Dependence of PTX3 on serum glucose levels was more pronounced in women with GDM than in the NGT group. This notion together with its inverse relation to the parameters of insulin sensitivity, suggests a potential involvement of PTX3 in GDM pathology. [ABSTRACT FROM AUTHOR]

Objective: Progranulin (PGRN) was recently introduced as a novel marker of chronic inflammatory response in obesity and type 2 diabetes capable of directly affecting the insulin signaling pathway. This study aimed to investigate the role of PGRN in gestational diabetes mellitus (GDM), which is regarded as a model for early type 2 diabetes. Methods: PGRN serum levels were measured in 90 pregnant women (45 GDM and 45 normal glucose tolerance (NGT)). In addition, PGRN was measured during a 2-h, 75 g oral glucose tolerance test in 20 pregnant women (ten GDM and ten NGT) and in 16 of them post partum (ten GDM and six NGT). Results: PGRN concentrations were significantly higher in pregnant women compared with post partum levels (536.79 + 31.81 vs 241.53 + 8.86, P< 0.001). Multivariate regression analyses showed a strong positive correlation of PGRN with estrogen and progesterone. The insulinogenic index, a marker of early insulin secretion, displayed a positive correlation with PGRN, both during and after pregnancy (R = 0.47, P = 0.034; R = 0.63, P = 0.012). HbA1c and the oral glucose insulin sensitivity index showed significant post partum associations with PGRN (R = 0.43, P = 0.049; R= -- 0.65, P= 0.009). Conclusions: PGRN concentrations are markedly lower after pregnancy regardless of the gestational glucose tolerance state. PGRN levels per se do not discriminate between mild GDM and NGT in pregnant women. Therefore, the development of GDM appears to be due to impaired ß-cell function that is not related to PGRN effect. [ABSTRACT FROM AUTHOR]

Summary Objective To evaluate the relationship of plasma fetuin-A levels with markers of bone turnover in male and female type 2 diabetic subjects. Background Fetuin-A, which is a serum protein produced by the liver and promotes bone mineralization, is an independent risk factor for type 2 diabetes, whilst type 2 diabetes is associated with an increased incidence of osteoporosis or fractures. It is not known how fetuin-A levels relate to parameters of bone metabolism in type 2 diabetes. Design and patients Eighty patients with type 2 diabetes [40 men and 40 women matched for age, body mass index (BMI) and time since diagnosis of diabetes] were studied. Fetuin-A together with metabolic parameters and levels of serum carboxy-terminal telopeptide of type 1 collagen (C-telopeptide), osteocalcin, procollagen type 1 amino-terminal propeptide (P1NP), bone alkaline phosphatase (ALP) and sex hormones was determined in all participants. Results Fetuin-A levels did not differ significantly between male and female diabetic subjects. In a model adjusted for age, BMI, fatty liver index (FLI), time since diagnosis of diabetes, HbA 1c, antidiabetic and lipid-lowering drug therapies, smoking, total serum protein, creatinine, gamma glutamyl-transferase, parathyroid hormone, C-reactive protein, glomerular filtration rate, and presence of micro-, cardio-, and peripheral vascular diabetic complications, fetuin-A showed a significant positive association with levels of bone ALP ( r = 0·71, P = 0·006) in men. In women, fetuin-A was significantly negatively associated with C-telopeptide ( r = −0·60, P = 0·03) levels. Conclusions Results suggest an independent association of fetuin-A levels with markers of bone turnover in male and female patients with type 2 diabetes. More studies are needed to determine whether fetuin-A could serve as a new marker for fracture risk or osteoporosis in type 2 diabetes and to explore its potential sexually dimorphic effects. [ABSTRACT FROM AUTHOR]

Objective. Fetuin-A has been associated with gestational diabetes mellitus (GDM). We investigated fetuin-A levels during and after pregnancy in women with GDM. Fetuin-A measurements were performed in 10 women with GDM and 10 age and body mass index (BMI) matched healthy pregnant women. All women underwent an oral glucose tolerance test (OGTT) in and 3 months after gestation. Results. Fasting fetuin-A correlated with BMI in women with former GDM (r = 0.90, P < 0.0001) but showed no association with parameters of glucose tolerance in women with GDM or post-GDM. GDM featured significantly lower insulin sensitivity and higher insulin and C-peptide secretion profiles compared to NGT during pregnancy (P < 0.05). Fasting and postprandial fetuin-A did not differ between groups, neither during nor after pregnancy. Conclusion. Fetuin-A is not influenced by glucose tolerance during or after pregnancy or acute glucose elevations following glucose ingestion in young women, but closely relates to BMI early postpartum. [ABSTRACT FROM AUTHOR]

Objective: T cells and level of the cytokine interferon-γ (IFN-γ) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-γ and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis.Research Design and Methods: We used Hh reporter cells, cell lines, and primary adipocyte differentiation models to explore costimulation of IFN-γ and Hh signaling. Genetic dissection using Ifngr1(-/-) and Stat1(-/-) mouse embryonic fibroblasts, and ultimately, anti-IFN-γ neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context.Results: T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngr1(-/-) and Stat1(-/-) cells, and simultaneous activation of Hh and IFN-γ signaling, we showed that IFN-γ directly suppresses Hh stimulation, thus rescuing adipogenesis. We confirmed our findings using primary mouse and primary human (pre)adipocytes. Importantly, robust opposing signals for Hh and T-cell pathways in obese human adipose expression profiles and IFN-γ depletion in mice identify the system as intact in adipose tissue in vivo.Conclusions: These results identify a novel antagonistic cross-talk between IFN-γ and Hh signaling in white adipose tissue and demonstrate IFN-γ as a potent inhibitor of Hh signaling. [ABSTRACT FROM AUTHOR]

OBJECTIVE--T cells and level of the cytokine interferon-γ (IFN-γ) are increased in adipose tissue in obesity. Hedgehog (Hh) signaling has been shown to potently inhibit white adipocyte differentiation. In light of recent findings in neurons that IFN-γ/ and Hh signaling cross-talk, we examined their potential interaction in the context of adipogenesis. RESEARCH DESIGN AND METHODS--We used Hh reporter cells, cell fines, and primary adipocyte differentiation models to explore costimulation of IFN-γ/and Hh signaling. Genetic dissection using Ifngr1-/- and Stat1-/- mouse embryonic fibroblasts, and ultimately, anti-IFN-γ/neutralization and expression profiling in obese mice and humans, respectively, were used to place the findings into the in vivo context. RESULTS--T-cell supernatants directly inhibited hedgehog signaling in reporter and 3T3-L1 cells. Intriguingly, using blocking antibodies, Ifngr1-/- and Stat1-/- cells, and simultaneous activation of Hh and IFN-γ signaling, we showed that IFN-γ/directly suppresses Hh stimulation, thus rescuing adipogenesis. We confirmed our findings using primary mouse and primary human (pre)adipocytes. Importantly, robust opposing signals for Hh and T-cell pathways in obese human adipose expression profiles and IFN-γ/depletion in mice identify the system as intact in adipose tissue in vivo. CONCLUSIONS--These results identify a novel antagonistic cross-talk between IFN-γ and Hh signaling in white adipose tissue and demonstrate IFN-γ/ as a potent inhibitor of Hh signaling. [ABSTRACT FROM AUTHOR]

Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. In this study, we isolated stromal vascular cells and ATMs from human adipose tissue of different locations. We phenotypically and functionally characterized ATMs for surface marker expression, endocytosis and cytokine production. For comparison, we used macrophages of the "classical" (M1) and the "alternative" anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Alike prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, hemoglobin scavenger receptor CD163, and integrin alphavbeta5. The number of cells expressing these molecules significantly correlated with BMI. Notably, stromal vascular cells positive for the common monocyte/macrophage marker CD14 included a considerable proportion of blood monocytes whose abundance did not correlate with BMI, pointing to the requirement for additional surface markers such as those analyzed here to identify ATMs. ATMs showed endocytic activities similar to M2 macrophages and secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNFalpha, IL-6, IL-1, MCP-1, and MIP-1 alpha was even higher in ATMs than in pro-inflammatory M1 macrophages. In conclusion, ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but ATMs are competent to produce extensive amounts of inflammatory cytokines that could considerably contribute to the development of insulin resistance in obese patients. [ABSTRACT FROM AUTHOR]

The author index of "Obesity 2010 Abstract Supplement," is presented.