Bruce M. Spiegelman

Bio: Bruce M. Spiegelman is an academic researcher from Harvard University. The author has contributed to research in topics: Adipose tissue & Peroxisome proliferator-activated receptor. The author has an hindex of 179, co-authored 434 publications receiving 158009 citations. Previous affiliations of Bruce M. Spiegelman include University of California, San Francisco & Vassar College.

Differentiation-dependent stimulation of neovascularization and endothelial cell chemotaxis by 3T3 adipocytes.

Abstract: 3T3 cells that have undergone adipose differentiation in vitro secrete factor(s) that stimulate angiogenesis (neovascularization) in vivo. When medium containing 0.5% fetal calf serum was conditioned by 3T3-F442A adipocytes, it stimulated angiogenesis when placed on the chicken chorioallantoic membrane. Control medium or medium conditioned by preadipocytes did not stimulate angiogenesis, even at much higher doses. Thus, the production of the angiogenic activity is strongly dependent upon differentiation of the adipocytes. The degree of the angiogenic response to adipocyte-conditioned medium was potentiated by heparin; heparin added to unconditioned medium or to preadipocyte-conditioned medium was not angiogenic. The adipocyte-conditioned medium also strongly stimulated, in a differentiation-dependent fashion, the motility of aortic and capillary endothelial cells in a modified Boyden chamber assay. Checkerboard analysis cells indicated that 75% of the motility-stimulating activity was chemotactic in nature. The chemotactic activity has an apparent specificity for endothelial cells, in that chemotaxis of smooth muscle cells and fibroblasts was stimulated to a much lesser extent. These results, in conjunction with our previous demonstration of an endothelial cell mitogen produced by 3T3 adipocytes [Castellot, J. J., Jr., Karnovsky, M. J. & Spiegelman, B. M. (1980) Proc. Natl. Acad. Sci. USA 77, 6007-6011] indicate that the differentiation of these cells is closely linked to the production of factors that stimulate angiogenesis in vivo and growth and chemotaxis of endothelial cells in vitro.

A potential role for the nuclear factor of activated T cells family of transcriptional regulatory proteins in adipogenesis.

Abstract: NFAT (nuclear factor of activated T cells) is a family of transcription factors implicated in the control of cytokine and early immune response gene expression. Recent studies have pointed to a role for NFAT proteins in gene regulation outside of the immune system. Herein we demonstrate that NFAT proteins are present in 3T3-L1 adipocytes and, upon fat cell differentiation, bind to and transactivate the promoter of the adipocyte-specific gene aP2. Further, fat cell differentiation is inhibited by cyclosporin A, a drug shown to prevent NFAT nuclear localization and hence function. Thus, these data suggest a role for NFAT transcription factors in the regulation of the aP2 gene and in the process of adipocyte differentiation.

PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erbα axis

Abstract: FGF21 is a hormone produced in liver and fat that dramatically improves peripheral insulin sensitivity and lipid metabolism. We show here that obese mice with genetically reduced levels of a key hepatic transcriptional coactivator, PGC-1α, have improved whole-body insulin sensitivity with increased levels of hepatic and circulating FGF21. Gain- and loss-of-function studies in primary mouse hepatocytes show that hepatic FGF21 levels are regulated by the expression of PGC-1α. Importantly, PGC-1α-mediated reduction of FGF21 expression is dependent on Rev-Erbα and the expression of ALAS-1. ALAS-1 is a PGC-1α target gene and the rate-limiting enzyme in the synthesis of heme, a ligand for Rev-Erbα. Modulation of intracellular heme levels mimics the effect of PGC-1α on FGF21 expression, and inhibition of heme biosynthesis completely abrogates the down-regulation of FGF21 in response to PGC-1α. Thus, PGC-1α can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand.

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

limma powers differential expression analyses for RNA-sequencing and microarray studies

Abstract: limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Obesity is associated with macrophage accumulation in adipose tissue

Abstract: Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.