The Effect of Macrophage-secreted Factors on Preadipocyte Survival

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dc.contributor.authorMolgat, André
dc.date.accessioned2013-01-10T14:53:58Z
dc.date.available2013-01-10T14:53:58Z
dc.date.created2013
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10393/23628
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-6294
dc.description.abstractAdipose tissue (AT) expansion and remodeling that maintains healthy function relies on stromal preadipocytes capable of differentiating into new adipocytes (adipogenesis). During chronic positive energy balance, a relative deficit in adipogenesis, from either a decrease in preadipocyte number or their capacity to differentiate, leads to excessive adipocyte hypertrophy and AT dysfunction. AT contains macrophages whose number and activation state is dynamically regulated with changes in AT mass. This study aims to investigate the effect of macrophage-secreted factors on preadipocyte survival. To assess the effect of macrophage-secreted factors on preadipocytes, murine 3T3-L1 preadipocytes or human primary preadipocytes were incubated with macrophage-conditioned medium (MacCM), prepared from either murine (J774A.1, RAW264.7, bone marrow-derived) or human (THP-1, monocyte-derived) macrophage models, respectively. MacCM inhibited preadipocyte apoptosis and activated pro-survival signaling in both preadipocyte models. Inhibition of PDGFR, Akt, or ERK1/2 reduced the pro-survival effect of MacCM in 3T3-L1 preadipocytes. Inhibition of reactive oxygen species (ROS) generation, or enhancement of ROS clearance, reduced MacCM-dependent 3T3-L1 preadipocyte survival. Whereas anti-inflammatory activated macrophages retained the ability to prevent preadipocyte apoptosis, pro-inflammatory activated macrophages did not. TNF-α immunoneutralization restored the survival activity of pro-inflammatory MacCM on 3T3-L1 preadipocytes. These studies reveal a novel pro-survival effect of MacCM on preadipocytes, and identify signaling molecules (PDGF, Akt, ERK1/2, and ROS) that underlie this action. Macrophage activation was found to regulate the pro-survival activity of MacCM. These in vitro cell culture studies are consistent with a model in which the extent of preadipocyte apoptosis in vivo may determine preadipocyte number and the ability of AT to expand while maintaining healthy function during chronic positive energy balance.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectadipocyte
dc.subjectpreadipocyte
dc.subjectmetabolism
dc.subjectadipose tissue
dc.subjectfat
dc.subjectmacrophage
dc.subjectinflammation
dc.subjectPDGF
dc.subjectTNFalpha
dc.subjectapoptosis
dc.subjectreactive oxygen species
dc.subjectplatelet-derived growth factor
dc.subjecttumor-necrosis factor alpha
dc.titleThe Effect of Macrophage-secreted Factors on Preadipocyte Survival
dc.typeThesis
dc.faculty.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
dc.contributor.supervisorSorisky, Alexander
dc.embargo.termsimmediate
dc.degree.namePhD
dc.degree.leveldoctorate
dc.degree.disciplineMédecine / Medicine
thesis.degree.namePhD
thesis.degree.levelDoctoral
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
CollectionThèses, 2011 - // Theses, 2011 -

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