Publications by authors named "Vivian M Benoit"

8 Publications

  • Page 1 of 1

RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice.

Diabetes 2014 Jun 11;63(6):1948-65. Epub 2014 Feb 11.

Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY

In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.
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http://dx.doi.org/10.2337/db13-1636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030112PMC
June 2014

GRP78 plays an essential role in adipogenesis and postnatal growth in mice.

FASEB J 2013 Mar 24;27(3):955-64. Epub 2012 Nov 24.

Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Rm. 5308, Los Angeles, CA 90089-9176, USA.

To investigate the role of GRP78 in adipogenesis and metabolic homeostasis, we knocked down GRP78 in mouse embryonic fibroblasts and 3T3-L1 preadipocytes induced to undergo differentiation into adipocytes. We also created an adipose Grp78-knockout mouse utilizing the aP2 (fatty acid binding protein 4) promoter-driven Cre-recombinase. Adipogenesis was monitored by molecular markers and histology. Tissues were analyzed by micro-CT and electron microscopy. Glucose homeostasis and cytokine analysis were performed. Our results indicate that GRP78 is essential for adipocyte differentiation in vitro. aP2-cre-mediated GRP78 deletion leads to lipoatrophy with ∼90% reduction in gonadal and subcutaneous white adipose tissue and brown adipose tissue, severe growth retardation, and bone defects. Despite severe abnormality in adipose mass and function, adipose Grp78-knockout mice showed normal plasma triglyceride levels, and plasma glucose and insulin levels were reduced by 40-60% compared to wild-type mice, suggesting enhanced insulin sensitivity. The endoplasmic reticulum is grossly expanded in the residual mutant white adipose tissue. Thus, these studies establish that GRP78 is required for adipocyte differentiation, glucose homeostasis, and balanced secretion of adipokines. Unexpectedly, the phenotypes and metabolic parameters of the mutant mice, which showed early postnatal mortality, are uniquely distinct from previously characterized lipodystrophic mouse models.
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http://dx.doi.org/10.1096/fj.12-213330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574283PMC
March 2013

Allelic variation of the Lyme disease spirochete adhesin DbpA influences spirochetal binding to decorin, dermatan sulfate, and mammalian cells.

Infect Immun 2011 Sep 27;79(9):3501-9. Epub 2011 Jun 27.

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

After transmission by an infected tick, the Lyme disease spirochete, Borrelia burgdorferi sensu lato, colonizes the mammalian skin and may disseminate systemically. The three major species of Lyme disease spirochete--B. burgdorferi sensu stricto, B. garinii, and B. afzelii--are associated with different chronic disease manifestations. Colonization is likely promoted by the ability to bind to target tissues, and Lyme disease spirochetes utilize multiple adhesive molecules to interact with diverse mammalian components. The allelic variable surface lipoprotein decorin binding protein A (DbpA) promotes bacterial binding to the proteoglycan decorin and to the glycosaminoglycan (GAG) dermatan sulfate. To assess allelic variation of DbpA in GAG-, decorin-, and cell-binding activities, we expressed dbpA alleles derived from diverse Lyme disease spirochetes in B. burgdorferi strain B314, a noninfectious and nonadherent strain that lacks dbpA. Each DbpA allele conferred upon B. burgdorferi strain B314 the ability to bind to cultured kidney epithelial (but not glial or endothelial) cells, as well as to purified decorin and dermatan sulfate. Nevertheless, allelic variation of DbpA was associated with dramatic differences in substrate binding activity. In most cases, decorin and dermatan sulfate binding correlated well, but DbpA of B. afzelii strain VS461 promoted differential binding to decorin and dermatan sulfate, indicating that the two activities are separable. DbpA from a clone of B. burgdorferi strain N40 that can cause disseminated infection in mice displayed relatively low adhesive activity, indicating that robust DbpA-mediated adhesive activity is not required for spread in the mammalian host.
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http://dx.doi.org/10.1128/IAI.00163-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165495PMC
September 2011

Genetic control of the innate immune response to Borrelia hermsii influences the course of relapsing fever in inbred strains of mice.

Infect Immun 2010 Feb 7;78(2):586-94. Epub 2009 Dec 7.

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Host susceptibility to infection is controlled in large measure by the genetic makeup of the host. Spirochetes of the genus Borrelia include nearly 40 species of vector-borne spirochetes that are capable of infecting a wide range of mammalian hosts, causing Lyme disease and relapsing fever. Relapsing fever is associated with high-level bacteremia, as well as hematologic manifestations, such as thrombocytopenia (i.e., low platelet numbers) and anemia. To facilitate studies of genetic control of susceptibility to Borrelia hermsii infection, we performed a systematic analysis of the course of infection using immunocompetent and immunocompromised inbred strains of mice. Our analysis revealed that sensitivity to B. hermsii infections is genetically controlled. In addition, whereas the role of adaptive immunity to relapsing fever-causing spirochetes is well documented, we found that innate immunity contributes significantly to the reduction of bacterial burden. Similar to human infection, the progression of the disease in mice was associated with thrombocytopenia and anemia. Histological and fluorescence in situ hybridization (FISH) analysis of infected tissues indicated that red blood cells (RBCs) were removed by tissue-resident macrophages, a process that could lead to anemia. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream by tissue phagocytes.
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http://dx.doi.org/10.1128/IAI.01216-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812184PMC
February 2010

In vitro CpG methylation increases the transformation efficiency of Borrelia burgdorferi strains harboring the endogenous linear plasmid lp56.

J Bacteriol 2008 Dec 10;190(24):7885-91. Epub 2008 Oct 10.

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Borrelia burgdorferi is the causative agent of Lyme disease, the most common vector-borne illness in the Northern hemisphere. Low-passage-number infectious strains of B. burgdorferi exhibit extremely low transformation efficiencies-so low, in fact, as to hinder the genetic study of putative virulence factors. Two putative restriction-modification (R-M) systems, BBE02 contained on linear plasmid 25 (lp25) and BBQ67 contained on lp56, have been postulated to contribute to this poor transformability. Restriction barriers posed by other bacteria have been overcome by the in vitro methylation of DNA prior to transformation. To test whether a methylation-sensitive restriction system contributes to poor B. burgdorferi transformability, shuttle plasmids were treated with the CpG methylase M.SssI prior to the electroporation of a variety of strains harboring different putative R-M systems. We found that for B. burgdorferi strains that harbor lp56, in vitro methylation increased transformation by at least 1 order of magnitude. These results suggest that in vitro CpG methylation protects exogenous DNA from degradation by an lp56-contained R-M system, presumably BBQ67. The utility of in vitro methylation for the genetic manipulation of B. burgdorferi was exemplified by the ease of plasmid complementation of a B. burgdorferi B31 A3 BBK32 kanamycin-resistant (B31 A3 BBK32::Kan(r)) mutant, deficient in the expression of the fibronectin- and glycosaminoglycan (GAG)-binding adhesin BBK32. Consistent with the observation that several surface proteins may promote GAG binding, the B. burgdorferi B31 A3 BBK32::Kan(r) mutant demonstrated no defect in the ability to bind purified GAGs or GAGs expressed on the surfaces of cultured cells.
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http://dx.doi.org/10.1128/JB.00324-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593207PMC
December 2008

Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia.

Int J Oncol 2006 Jun;28(6):1327-35

Medical Biotechnology Center, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark.

Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal breast epithelia, and the differential expression of a panel of candidate genes was further validated by quantitative PCR and immunohistochemical analysis of cell lines and tumor biopsies. A limited number of genes, including several members of the GAGE and insulin growth factor binding protein (IGFBP) gene families, Vav1, monoglyceride lipase and NADP+-dependent malic enzyme, exhibited altered expression in MCB vs. ductal breast cancer, and the differences for some of these genes were confirmed on an extended panel of cell lines by quantitative PCR. Immunohistochemical analysis further established that the expression of monoglyceride lipase was restricted to ductal breast cancer and present in 77% of these tumors, while Vav1 was restricted to MCB and present in 60% of tumors. In this study, we have identified genes that are differentially expressed in MCB vs. ductal breast cancer and further analysis of the gene products should illuminate the biological differences between MCB and ductal breast cancer.
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June 2006

Late-onset group B streptococcal infection in identical twins: insight to disease pathogenesis.

J Perinatol 2002 Jun;22(4):326-30

Division of Pediatric Infectious Diseases, University of California, San Diego, La Jolla, CA 92093, USA.

Late-onset group B streptococcal (GBS) infection affecting identical twins is described. Although exhibiting similar signs and symptoms at presentation, twin A suffered fulminant fatal meningitis while twin B recovered completely. The GBS isolates proved to be genetically identical and possessed equivalent abilities to invade and injure cells of the human blood-brain barrier in vitro. Clinical variables associated with the adverse outcome in twin A were longer duration of fever prior to antibiotics and the development of neutropenia. The case histories and experimental data are reviewed to underscore key features of GBS disease pathogenesis.
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http://dx.doi.org/10.1038/sj.jp.7210675DOI Listing
June 2002

Group B streptococcal beta-hemolysin/cytolysin promotes invasion of human lung epithelial cells and the release of interleukin-8.

J Infect Dis 2002 Jan 3;185(2):196-203. Epub 2002 Jan 3.

Department of Pediatrics, Division of Infectious Diseases, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.

Pneumonia and lung injury are hallmarks of early-onset neonatal group B streptococcal (GBS) infections. Production of a beta-hemolysin/cytolysin (beta-h/c) encoded by the cylE gene is associated with GBS virulence in vivo. To elucidate the contribution of the beta-h/c toxin to lung injury, the interactions of GBS wild-type strains and isogenic cylE mutants with A549 lung epithelial cells were examined. Compared with wild-type GBS strains, cylE mutants did not produce cytolytic injury, even at high inocula, and exhibited decreased cellular invasion. Additionally, cylE mutants induced less A549 cell release of the neutrophil chemoattractant interleukin (IL)-8. GBS invasion and IL-8 induction were significantly reduced in the presence of dipalmotyl phosphatidylcholine, a major constituent of lung surfactant and a known inhibitor of beta-h/c activity. These data indicate that the GBS beta-h/c contributes to invasion and immune activation of lung epithelial cells and may represent a multifunctional virulence factor in the early pulmonary stages of GBS infection.
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http://dx.doi.org/10.1086/338475DOI Listing
January 2002