Author
Bruce M. Spiegelman
Other affiliations: University of California, San Francisco, Vassar College, Indiana University ...read more
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.
Papers published on a yearly basis
Papers
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TL;DR: Data show that the PPARγ ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.
Abstract: Purpose: Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor ( EGFR ) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARγ ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARγ/carboplatin combination in these more relevant models of drug resistant non–small cell lung cancer.
Experimental Design: Tumorigenesis was induced by activation of either mutant KRAS or EGFR . Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed.
Results: Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity.
Conclusions: These data show that the PPARγ ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.
70 citations
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TL;DR: Analysis of AP-1 transcriptional activity in mouse keratinocytes treated with calcium and 12-O-tetradecanoyl phorbol-13-acetate indicates that Fra-2 and c-Fos play opposing roles in regulating AP- 1 activity in Keratinocytes and that multiple inducer-dependent regulatory pathways may exist for the expression of keratinocyte differentiation markers.
Abstract: The major differentiation products of maturing keratinocytes contain AP-1 regulatory motifs, and AP-1 DNA binding activity increases in cultured keratinocytes induced to differentiate by calcium. Here, we have analysed AP-1 transcriptional activity in mouse keratinocytes treated with calcium and 12-O-tetradecanoyl phorbol-13-acetate (TPA), two agents that induce terminal differentiation of keratinocytes with different phenotypic consequences. Reporter constructs representing multimers of AP-1 sequences found in keratinocyte marker genes demonstrated that the calcium-induced AP-1 DNA binding activity does not correlate with transcriptional activation. Moreover, expression from active subunits of the profilaggrin and spr 1 promoters increased in calcium-treated keratinocytes when the AP-1 sites were disrupted, indicating that AP-1 may negatively regulate certain promoters in these cells. In contrast, AP-1 reporter activity was increased in keratinocytes treated with TPA. This induction was dependent upon the expression of c-Fos since AP-1 transcriptional activity was not increased in TPA-treated keratinocytes derived from c-fos null mice. Analysis of AP-1 protein expression in calcium- and TPA-treated keratinocytes demonstrated that only TPA increased the expression of c-Jun, while Jun B and Jun D were induced by both of these agents. c-Fos was expressed only in TPA treated keratinocytes, Fra-2 was expressed only in calcium-treated cells, and Fra-1 was expressed in both. Exogenous expression of Fra-2 repressed AP-1 transcriptional activity in TPA-treated keratinocytes, while c-Fos expression activated the AP-1 sequence in calcium-treated keratinocytes. These data indicate that Fra-2 and c-Fos play opposing roles in regulating AP-1 activity in keratinocytes and that multiple inducer-dependent regulatory pathways may exist for the expression of keratinocyte differentiation markers.
69 citations
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TL;DR: These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.
Abstract: Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.
68 citations
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TL;DR: Several lines of evidence have now converged to identify the peroxisome proliferator–activated receptor γ (PPARγ) as the relevant molecular target of these compounds (4).
Abstract: One of the great ironies of the present-day industrialized world is serious disease and death brought about by too much rich food and too little physical exertion. The incidence of obesity has increased to the point that one in two American adults is now considered overweight (1). Pathologies linked to obesity, such as type 2 diabetes, hypertension, and cardiovascular disorders, are also increasingly prevalent in our society.
The tight linkage of obesity, insulin resistance (and frank diabetes), dyslipidemia, and hypertension has been widely observed and has been dignified with a label – syndrome X, or the metabolic syndrome (2). The exact pathogenic relationships between the component conditions of the metabolic syndrome are complex and incompletely understood, despite significant and ongoing efforts to identify susceptibility genes in human populations and animal models. The convergence of these conditions in the metabolic syndrome is not an area isolated to mere academic interest: Coronary and peripheral vascular disease leading to myocardial infarction and stroke is the unhappy fate of many affected individuals.
In an ideal world, the metabolic syndrome would be treated by diet and exercise, leading to weight loss. Even relatively modest degrees of weight loss have been shown to improve markers of the metabolic syndrome, such as blood pressure, serum cholesterol, and insulin levels. Unfortunately, most patients find the necessary dietary and exercise regimens to be difficult. Even if the difficulty is surmounted, they find that their bodies resist any deviation from the “set-point” of their elevated weight. Much emphasis, therefore, has been placed on treating the component conditions of the metabolic syndrome pharmacologically. Indeed, these efforts have been successful, and new medications for hypertension and dyslipidemia are now available that can reduce morbidity and mortality from cardiovascular disease in these patients.
The treatment of insulin resistance and diabetes has until recently been restricted to the administration of exogenous insulin or to sulfonylureas, which promote the release of endogenous insulin. Although effective at reducing serum glucose levels in diabetic patients, neither of these agents addresses the underlying insulin resistance at the core of the metabolic syndrome. In the last five years, however, metformin became available in the US. Metformin reduces insulin resistance primarily in the liver, although its precise molecular targets are not known. Unfortunately, the use of metformin in patients with significant renal, hepatic, or cardiac impairment can lead to life-threatening lactic acidosis, reducing the utility of this agent in many people with diabetes (3).
It was with considerable excitement, therefore, that the thiazolidinedione (TZD) drugs were introduced into the US market in the last five years. Like metformin, these antidiabetic agents, such as troglitazone (Rezulin™), rosiglitazone (Avandia™), and pioglitazone (Actos™), were originally developed without knowledge of their mechanism of action. Several lines of evidence, however, have now converged to identify the peroxisome proliferator–activated receptor γ (PPARγ) as the relevant molecular target of these compounds (4). Perhaps most convincing is the fact that non-TZD synthetic compounds isolated solely on the basis of binding to PPARγ, a ligand-activated transcriptional regulator, exert antidiabetic effects similar to those of the TZDs (5).
As discussed by Olefsky (6) and others in the recent JCI Perspective series on insulin resistance, TZDs reduce insulin resistance and improve glucose homeostasis in diabetic rodents and humans. Nevertheless, concerns remain about possible deleterious side effects of these drugs. Troglitazone, the first TZD approved, was shown to have hepatotoxic effects in some patients during postmarketing analysis (7). Unfortunately, this reaction was severe enough in a few patients to cause death or a requirement for liver transplantation, leading to the withdrawal of this drug from the US market. Thus far, monitoring of patients taking rosiglitazone and pioglitazone has not revealed significant hepatotoxicity suggesting that this undesired effect may be idiosyncratic to troglitazone and not related to the activation of PPARγ per se. A more precise understanding of the spectrum of side effects of rosiglitazone and pioglitazone must await more studies in larger numbers of patients.
One complicating feature in the use of PPARγ agonists is that the precise tissue targets relevant to metabolic disease are not fully understood. PPARγ is expressed at its highest levels in adipose tissue, with lower levels expressed in many cell types, including monocytes, skeletal muscle, vascular endothelial cells, and breast, colon, and prostate epithelium. PPARγ is a dominant regulator of many aspects of fat cell biology, including adipose cell differentiation, fatty acid uptake, and lipogenesis, raising the possibility that the insulin-sensitizing effects of TZDs reflect the increased performance of TZD-treated adipose tissue as a sink for both fat and glucose. On the other hand, it is entirely possible that TZDs act primarily through PPARγ in other tissues such as muscle, liver, or the β cells of the pancreas. Global deletion of the PPARγ gene in mice results in placental dysfunction and embryonic lethality (8, 9), so resolution of this question in a definitive way will require the construction of tissue-specific knockouts.
68 citations
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TL;DR: In this paper, a strategy for adipose-specific inactivation of loxP-floxed gene segments was developed, where cross-crossing of the aP2/ Cre mice with any loxp-FLO-ed gene will facilitate its functional analysis in adipose tissue.
Abstract: Functional analysis of mammalian genes relies, in part, on targeted mutations generated by homologous recombination in mice. We have developed a strategy for adipose-specific inactivation of loxP-floxed gene segments. Transgenic mice have been established that express Cre recombinase under the control of the adipose-specific aP2 enhancer/promoter. Crossing of the aP2/ Cre mice with any loxP-floxed gene will facilitate its functional analysis in adipose tissue.
67 citations
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
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.
34,830 citations
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TL;DR: The philosophy and design of the limma package is reviewed, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.
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.
22,147 citations
28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组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�ly.
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。
18,940 citations
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TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.
9,980 citations
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TL;DR: 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) found that the expression of 1,304 transcripts correlated significantly with body mass.
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.
8,902 citations