Mechanical homeostasis regulating adipose tissue volume

<p>Abstract</p> <p>Background</p> <p>The total body adipose tissue volume is regulated by hormonal, nutritional, paracrine, neuronal and genetic control signals, as well as components of cell-cell or cell-matrix interactions. There are no known locally acting homeostatic mechanisms by which growing adipose tissue might adapt its volume.</p> <p>Presentation of the hypothesis</p> <p>Mechanosensitivity has been demonstrated by mesenchymal cells in tissue culture. Adipocyte differentiation has been shown to be inhibited by stretching in vitro, and a pathway for the response has been elucidated. In humans, intermittent stretching of skin for reconstructional purposes leads to thinning of adipose tissue and thickening of epidermis – findings matching those observed in vitro in response to mechanical stimuli. Furthermore, protracted suspension of one leg increases the intermuscular adipose tissue volume of the limb. These findings may indicate a local homeostatic adipose tissue volume-regulating mechanism based on movement-induced reduction of adipocyte differentiation. This function might, during evolution, have been of importance in confined spaces, where overgrowth of adipose tissue could lead to functional disturbance, as for instance in the turtle. In humans, adipose tissue near muscle might in particular be affected, for instance intermuscularly, extraperitoneally and epicardially. Mechanical homeostasis might also contribute to protracted maintainment of soft tissue shape in the face and neck region.</p> <p>Testing of the hypothesis</p> <p>Assessment of messenger RNA-expression of human adipocytes following activity in adjacent muscle is planned, and study of biochemical and volumetric adipose tissue changes in man are proposed.</p> <p>Implications of the hypothesis</p> <p>The interpretation of metabolic disturbances by means of adipose tissue might be influenced. Possible applications in the head and neck were discussed.</p

Intrinsic regulation of hemangioma involution by platelet-derived growth factor

Infantile hemangioma is a vascular tumor that exhibits a unique natural cycle of rapid growth followed by involution. Previously, we have shown that hemangiomas arise from CD133+ stem cells that differentiate into endothelial cells when implanted in immunodeficient mice. The same clonally expanded stem cells also produced adipocytes, thus recapitulating the involuting phase of hemangioma. In the present study, we have elucidated the intrinsic mechanisms of adipocyte differentiation using hemangioma-derived stem cells (hemSCs). We found that platelet-derived growth factor (PDGF) is elevated during the proliferating phase and may inhibit adipocyte differentiation. hemSCs expressed high levels of PDGF-B and showed sustained tyrosine phosphorylation of PDGF receptors under basal (unstimulated) conditions. Inhibition of PDGF receptor signaling caused enhanced adipogenesis in hemSCs. Furthermore, exposure of hemSCs to exogenous PDGF-BB reduced the fat content and the expression of adipocyte-specific transcription factors. We also show that these autogenous inhibitory effects are mediated by PDGF receptor-β signaling. In summary, this study identifies PDGF signaling as an intrinsic negative regulator of hemangioma involution and highlights the therapeutic potential of disrupting PDGF signaling for the treatment of hemangiomas

Genome-Wide Profiling of MicroRNAs in Adipose Mesenchymal Stem Cell Differentiation and Mouse Models of Obesity

In recent years, there has been accumulating evidence that microRNAs are key regulator molecules of gene expression. The cellular processes that are regulated by microRNAs include e.g. cell proliferation, programmed cell death and cell differentiation. Adipocyte differentiation is a highly regulated cellular process for which several important regulating factors have been discovered, but still not all are known to fully understand the underlying mechanisms. In the present study, we analyzed the expression of 597 microRNAs during the differentiation of mouse mesenchymal stem cells into terminally differentiated adipocytes by real-time RT-PCR. In total, 66 miRNAs were differentially expressed in mesenchymal stem cell-derived adipocytes compared to the undifferentiated progenitor cells. To further study the regulation of these 66 miRNAs in white adipose tissue in vivo and their dependence on PPARγ activity, mouse models of genetically or diet induced obesity as well as a mouse line expressing a dominant negative PPARγ mutant were employed

Meta-analysis: Neither quick nor easy

BACKGROUND: Meta-analysis is often considered to be a simple way to summarize the existing literature. In this paper we describe how a meta-analysis resembles a conventional study, requiring a written protocol with design elements that parallel those of a record review. METHODS: The paper provides a structure for creating a meta-analysis protocol. Some guidelines for measurement of the quality of papers are given. A brief overview of statistical considerations is included. Four papers are reviewed as examples. The examples generally followed the guidelines we specify in reporting the studies and results, but in some of the papers there was insufficient information on the meta-analysis process. CONCLUSIONS: Meta-analysis can be a very useful method to summarize data across many studies, but it requires careful thought, planning and implementation

Identification of New Genes Involved in Human Adipogenesis and Fat Storage

Since the worldwide increase in obesity represents a growing challenge for health care systems, new approaches are needed to effectively treat obesity and its associated diseases. One prerequisite for advances in this field is the identification of genes involved in adipogenesis and/or lipid storage. To provide a systematic analysis of genes that regulate adipose tissue biology and to establish a target-oriented compound screening, we performed a high throughput siRNA screen with primary (pre)adipocytes, using a druggable siRNA library targeting 7,784 human genes. The primary screen showed that 459 genes affected adipogenesis and/or lipid accumulation after knock-down. Out of these hits, 333 could be validated in a secondary screen using independent siRNAs and 110 genes were further regulated on the gene expression level during adipogenesis. Assuming that these genes are involved in neutral lipid storage and/or adipocyte differentiation, we performed InCell-Western analysis for the most striking hits to distinguish between the two phenotypes. Beside well known regulators of adipogenesis and neutral lipid storage (i.e. PPARγ, RXR, Perilipin A) the screening revealed a large number of genes which have not been previously described in the context of fatty tissue biology such as axonemal dyneins. Five out of ten axonemal dyneins were identified in our screen and quantitative RT-PCR-analysis revealed that these genes are expressed in preadipocytes and/or maturing adipocytes. Finally, to show that the genes identified in our screen are per se druggable we performed a proof of principle experiment using an antagonist for HTR2B. The results showed a very similar phenotype compared to knock-down experiments proofing the “druggability”. Thus, we identified new adipogenesis-associated genes and those involved in neutral lipid storage. Moreover, by using a druggable siRNA library the screen data provides a very attractive starting point to identify anti-obesity compounds targeting the adipose tissue

Determinants of abstract acceptance for the Digestive Diseases Week – a cross sectional study

BACKGROUND: The Digestive Diseases Week (DDW) is the major meeting for presentation of research in gastroenterology. The acceptance of an abstract for presentation at this meeting is the most important determinant of subsequent full publication. We wished to examine the determinants of abstract acceptance for this meeting. METHODS: A cross-sectional study was performed, based on abstracts submitted to the DDW. All 17,205 abstracts submitted from 1992 to 1995 were reviewed for acceptance, country of origin and research type (controlled clinical trials (CCT), other clinical research (OCR), basic science (BSS)). A random sub-sample (n = 1,000) was further evaluated for formal abstract quality, statistical significance of study results and sample size. RESULTS: 326 CCT, 455 OCR and 219 BSS abstracts were evaluated in detail. Abstracts from N/W Europe (OR 0.4, 95% CI 0.3–0.6), S/E Europe (OR 0.4, 95% CI 0.2–0.6) and non-Western countries (OR 0.3, 95% CI 0.2–0.5) were less likely to be accepted than North-American contributions when controlling for research type. In addition, the OR for the acceptance for studies with negative results as compared to those with positive results was 0.4 (95% CI 0.3–0.7). A high abstract quality score was also weakly associated with acceptance rates (OR 1.4, 95% CI 1.0–2.0). CONCLUSIONS: North-American contributions and reports with statistically positive results have higher acceptance rates at the AGA. Formal abstract quality was also predictive for acceptance

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Pharmacological targeting of apelin impairs glioblastoma growth

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours, a subpopulation of highly plastic self-renewing cancer cells exist that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such angiocrine signals remains unknown. Here, we deployed a mass spectrometry proteomic approach to characterise the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties (GSCs). Genetic and pharmacological targeting of apelin cognate receptor APLNR abrogates apelin- and endothelial-mediated expansion of GSCs and suppresses tumour initiation and growth. Functionally, selective competitive antagonists of APLNR were shown to be safe and effective in lengthening the survival of intracranially xenografted mice. Therefore, the APLN/APLNR signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.WT107715/Z/15/