CHUNG, SOONKYU, Ph. D. Mechanisms by Which Conjugated ...

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Figure 4. 9. LPS-induced inflammation in preadipocytes suppresses PPARγ activity and insulin sensitivity in adipocytes. Our results suggest that preadipocytes are more susceptible targets to LPS, increasing cytokine expression though NFκB and MAPK pathway. In turn, secreted cytokines activate NFκB and MAPK signaling in adipocytes leading to suppression of PPARγ activity, target gene expression (Glut4, glucose transporter 4; APM-1, adiponectin; aP2, adipocyte-specific fatty acid binding protein; SCD, stearoyl-coA desaturase; FAS, fatty acid syntase; PLIN, perilipin), and insulin sensitivity. 117
Discussion Adipose tissue is a source of mediators of inflammation and insulin resistance. We previously demonstrated that a dietary trans fatty acid (i.e., trans-10, cis-12 conjugated linoleic acid) induced IL-6 and IL-8 production predominantly from non-adipocytes, which was associated with insulin resistance in cultures of newly differentiated human adipocytes (Brown et al. 2004; Chung et al. 2005). By inducing acute inflammation with LPS in this study, we demonstrate for the first time that preadipocytes are the primary source of proinflammatory cytokines in these cultures (Fig 4.1-4.4), transmitting paracrine signals to neighboring adipocytes that suppress glucose uptake (Fig 4.5) and PPARγ activity (Fig 4.6) via NFκB and MAPK signaling (Fig 4.7-4.8). Based on these data, we propose a working model in Fig 4.9 showing that LPS initiates proinflammatory signaling through TLRs primarily in preadipocytes, which triggers activation of NFκB, MAPK, and PI3K pathways resulting in cytokine (i.e., TNF-α, IL-6, IL-8) production in preadipocytes. These cytokines, in turn, activate their cognate cell surface receptors on both adipocytes and preadipocytes, further augmenting cytokine production. In adipocytes, cytokine activation of NFκB, MEK/ERK, and JNK leads to decreased PPARγ activity, possibly by increasing PPARγ phosphorylation, thereby attenuating PPARγ target gene expression and insulin-stimulated glucose uptake. Characterization of Non-Adipocytes in the Cultures WAT is composed of several cell types. Of the cells residing in WAT, mature adipocytes are by far the largest in size, but their abundance depends on the specific 118
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CHUNG, SOONKYU, Ph. D. Mechanisms b
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MECHANISMS BY WHICH CONJUGATED LINO
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APPROVAL PAGE This Dissertation has
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I also would like to thank The Univ
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IV. PREADIPOCYTES MEDIATE LPS-INDUC
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LIST OF FIGURES ix Page Figure 1.1.
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Figure 4.7. LPS-induced NFκB activ
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in animals and some humans (reviewe
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CLA is potentially effective in: 1)
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Anti-adipogenic Mechanisms of CLA T
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2005). Chapter II of this dissertat
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Figure 1. 2. Multiple mechanisms by
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In contrast, studies conducted in a
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activation. Similarly, Chen et al.
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Central Hypothesis and Specific Obj
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CHAPTER II TRANS-10, CIS-12 CLA INC
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of MEK/ERK signaling by trans-10, c
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Materials and Methods Materials All
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the cultures for additional 12 h. A
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precipitated with ethanol, dried, a
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or for 30 min with 10 µM isoproter
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either 30 µM cis-9, trans-11 CLA o
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dependent effects of CLA on the pho
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Rapamycin Blocks CLA’s Increase i
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Figure 2. 2. Trans-10, cis-12 CLA a
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Figure 2. 4. Trans-10, cis-12 CLA a
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Figure 2. 6. Trans-10, cis-12 CLA i
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Figure 2. 8. Trans-10, cis-12 CLA-i
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Discussion Feeding mixed CLA isomer
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in lipolysis may occur via an ERK-d
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espectively, by the MEK inhibitor U
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Furthermore, the CLA-mediated incre
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proteins. Inhibition of NFκB activ
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Sopasakis et al. 2004) and insulin
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antibodies for anti-glyceraldehydre
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pM of human insulin in the presence
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were (accession #NM000600) sense (5
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Transfection efficiency was examine
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treatment (Brown et al. 2004), we d
Page 79 and 80: myotubes (Sinha et al. 2004; Weiger
Page 81 and 82: controls was found in cytosol (Fig
Page 83 and 84: Depletion of NFκB p65 by RNAi Atte
Page 85 and 86: eports of cytokine-mediated insulin
Page 87 and 88: Figure 3. 2. Trans-10, cis-12 CLA i
Page 89 and 90: Figure 3. 4. Trans-10, cis-12 CLA a
Page 91 and 92: Figure 3. 6. Trans-10, cis-12 CLA-i
Page 93 and 94: Figure 3. 8. Specific depletion of
Page 95 and 96: Figure 3. 10. Working model: Trans-
Page 97 and 98: Based on our working model (Fig 3.1
Page 99 and 100: mRNA levels of TNF-α (Fig. 3). How
Page 101 and 102: humans (Riserus et al. 2004a), and
Page 103 and 104: most likely not impairing the diffe
Page 105 and 106: 1) decreased adipogenic gene expres
Page 107 and 108: adipocytes from WAT in inflammation
Page 109 and 110: differentiation, cultures of SV cel
Page 111 and 112: Immunoblotting and 4MUrea-SDS-PAGE
Page 113 and 114: activity was measured using the Dua
Page 115 and 116: macrophages and myocytes, respectiv
Page 117 and 118: cultures, insulin’s stimulation o
Page 119 and 120: AD90 cultures treated with LPS. Con
Page 121 and 122: Table 4.1. List of human-gene speci
Page 123 and 124: Figure 4.2. Primary cultures of new
Page 125 and 126: Figure 4.4 LPS induction of cytokin
Page 127 and 128: Figure 4. 6. LPS suppresses PPARγ
Page 129: Figure 4. 8. Inhibitors of NFκB at
Page 133 and 134: To determine if non-adipocytes othe
Page 135 and 136: attenuation of insulin sensitivity
Page 137 and 138: epression of NFκB target gene expr
Page 139 and 140: EPILOGUE The “Obesity epidemic’
Page 141 and 142: Apart from our initial goal for thi
Page 143 and 144: Concerning membrane specific recept
Page 145 and 146: esearch topic I would like to exami
Page 147 and 148: Berg, A.H., Lin, Y., Lisanti, M.P.,
Page 149 and 150: Chen, C., Koh, A.J., Datta, N.S., Z
Page 151 and 152: Diradourian, C., Girard, J., and Pe
Page 153 and 154: Granlund, L., Juvet, L.K., Pedersen
Page 155 and 156: Imamura, M., Inoguchi, T., Ikuyama,
Page 157 and 158: Loscher, C.E., Draper, E., Leavy, O
Page 159 and 160: Piper, R.C., Hess, L.J., and James,
Page 161 and 162: Sinha, S., Perdomo, G., Brown, N.F.
Page 163 and 164: Vanden Berghe, W., Vermeulen, L., D
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