Charlie Foster

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

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Publications (3)12.33 Total impact

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    ABSTRACT: When adipose tissue accumulates in obesity, the ability of preadipocytes to differentiate permits a hyperplastic expansion of functional adipocytes that preserves insulin sensitivity. Adipose infiltration by macrophages is associated with an adipogenic deficit and the appearance of inflamed, insulin-resistant hypertrophied adipocytes. Interleukin (IL)-1β has been reported to account for the anti-adipogenic action of macrophages in a mouse model. Using the THP-1 human macrophage cell line and human primary preadipocytes, our objective was to determine if IL-1β was necessary for the ability of conditioned medium from THP-1 macrophages (THP-1-MacCM) to 1) stimulate human preadipocyte inhibitor of κB kinase (IKK) β and 2) inhibit human adipocye differentiation. IL-1β is present in THP-1-MacCM, and THP-1-MacCM or IL-1β (500 pg/ml; its concentration in THP-1-MacCM) acutely stimulated IKKβ phosphorylation and inhibitor of κB (IκB) degradation in preadipocytes. IL-1β was sufficient to inhibit adipogenesis on its own, and this was blocked by sc-514, an inhibitor of IKKβ, as has been reported for THP-1-MacCM. IκB degradation by IL-1β-immunodepleted THP-1-MacCM was attenuated, whereas IKKβ phosphorylation and inhibition of adipocyte differentiation was unchanged. Therefore, in contrast to what has been suggested for mouse cell models, IL-1β is not required for the ability of MacCM to inhibit adipogenesis in human cell models.
    Journal of Endocrinology 03/2013; · 4.06 Impact Factor
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    ABSTRACT: Adipose tissue contains macrophages whose state of activation is regulated as obesity develops. Macrophage-secreted factors influence critical processes involved in adipose tissue homeostasis, including preadipocyte proliferation and differentiation into adipocytes. Macrophage-conditioned medium (MacCM) from J774A.1 macrophages protects 3T3-L1 preadipocytes from apoptosis through platelet-derived growth factor (PDGF) signaling. Here, we investigated the effect of macrophage activation on MacCM-dependent preadipocyte survival. MacCM was prepared following activation of either J774A.1 macrophages with lipopolysaccharide (LPS) or human primary monocyte-derived macrophages (MD-macrophages) with LPS or interleukin 4 (IL4). 3T3-L1 and human primary preadipocytes were induced to undergo apoptosis in MacCM, and apoptosis was quantified by cell enumeration or Hoechst nuclear staining. Preadipocyte PDGF signaling was assessed by immunoblot analysis of phosphorylated PDGF receptor, Akt, and ERK1/2. Pro-inflammatory activation of J774A.1 macrophages with LPS inhibited the pro-survival activity of MacCM on 3T3-L1 preadipocytes, despite intact PDGF signaling. Upregulation of macrophage tumor necrosis factor a (TNFα) expression occurred in response to LPS, and TNFα was demonstrated to be responsible for the inability of LPS-J774A.1-MacCM to inhibit preadipocyte apoptosis. Furthermore, MacCM from human MD-macrophages (MD-MacCM) inhibited apoptosis of primary human preadipocytes. MD-MacCM from LPS-treated macrophages, but not IL4-treated anti-inflammatory macrophages, was unable to protect human preadipocytes from cell death. In both murine cell lines and human primary cells, pro-inflammatory activation of macrophages inhibits their pro-survival activity, favoring preadipocyte death. These findings may be relevant to preadipocyte fate and adipose tissue remodeling in obesity.
    Journal of Endocrinology 05/2012; 214(1):21-9. · 4.06 Impact Factor
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    ABSTRACT: Macrophage infiltration into adipose tissue, associated with obesity, is thought to contribute to abnormal adipose tissue remodeling, low-grade inflammation, and insulin resistance. Medium conditioned by macrophages (MacCM) inhibits 3T3-L1 and human adipocyte differentiation, as well as early adipogenic cell cycle events including MCE and retinoblastoma protein (Rb) phosphorylation. Our objective was to determine if the inhibition of Rb phosphorylation was linked to changes in cell cycle-related proteins. We treated 3T3-L1 preadipocytes with adipogenic inducers for 24 h in control medium versus J774A.1-MacCM. The differentiation-induced mRNA and protein expression of cyclin A, an activator of cyclin-dependent kinase (cdk) 2 which phosphorylates Rb, was inhibited by 82% and 73%, respectively, by J774A.1-MacCM; adipogenic expression of Myc, a transcriptional regulator of cyclin A, was also suppressed significantly. Consistent with the reduction in cyclin A levels, the activation of cdk2 by adipogenic inducers was inhibited by 75% by J774A.1-MacCM. J774A.1-MacCM also lowered levels of cyclins D1 and D2. Inhibition studies demonstrated that platelet-derived growth factor, an anti-adipogenic factor found in J774A.1-MacCM, was not responsible for the inhibitory effect on differentiation. The anti-adipogenic effect of J774A.1-MacCM was resistant to proteinase K and heat treatment, and was present in a <3 kDa fraction. Our data indicate that J774A.1-MacCM interferes with the upregulation of cyclin A levels and cdk2 activity that are required for Rb phosphorylation and MCE in 3T3-L1 adipogenesis.
    Journal of Cellular Physiology 09/2011; 226(9):2297-306. · 4.22 Impact Factor

Publication Stats

12 Citations
12.33 Total Impact Points

Institutions

  • 2013
    • Ottawa Hospital Research Institute
      • Chronic Disease Program
      Ottawa, Ontario, Canada
  • 2011–2012
    • University of Ottawa
      • • Department of Medicine
      • • Department of Biochemistry, Microbiology and Immunology
      Ottawa, Ontario, Canada