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

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Figure 3. 9. Depletion of NFκB p65 attenuates CLA’s suppression of Glut4 levels and insulin-stimulated glucose uptake. A: Cultures of differentiated human adipocytes were transfected with either control siRNA (siCon) or NFκB p65 siRNA (siP65) as described in Fig 3.8, and 72 h later were treated with BSA vehicle or 30 µM trans-10, cis-12 CLA (CLA) for 24 h. Basal and insulin-stimulated uptake of 4 nmol [ 3 H]-2-deoxy-glucose were measured for 90 min in the presence or absence of 100 nM human insulin. The basal control rate was ~100 pmol/(h·mg of protein). Data are normalized to the basal vehicle control’s (BSA, - insulin) rate. Means (+ S.E.; n=4) not sharing common superscript differ, p
Figure 3. 10. Working model: Trans-10, cis-12 CLA reduces glucose and fatty acid uptake and TG synthesis via activation of NFκB and ERK1/2 signaling and cytokine production. Upon entry into SV cells, trans-10, cis-12 CLA generates an unidentified signal, there<strong>by</strong> activating NFκB and ERK1/2. NFκB p65/p50 then translocates to the nucleus where it is activated <strong>by</strong> P-ERK. Activated NFκB initiates the transcription of specific cytokines (i.e., TNF-α, IL-6, IL-8). These secreted cytokines, in turn, activate their cognate cell surface receptors on adipocytes, leading to NFκB and ERK1/2 activation. NFκB p65/p50 translocates into the nucleus where P-ERK activates NFκB p65 and other transcription factors (TF), leading to suppression of PPARγ activity and target gene expression including aP2, sterol-CoA desaturase (SCD), lipoprotein lipase (LPL), fatty acid synthase (FAS), glucose transporter 4 (Glut4) and perilipin (PLIN). CLA may also generate an unidentified signal in adipocytes that activates NFκB and ERK1/2, which further suppresses PPARγ target gene expression. Together, this leads to adipocyte delipidation via decreased glucose and fatty acid uptake and TG synthesis. 82
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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
Page 43 and 44: either 30 µM cis-9, trans-11 CLA o
Page 45 and 46: dependent effects of CLA on the pho
Page 47 and 48: Rapamycin Blocks CLA’s Increase i
Page 49 and 50: Figure 2. 2. Trans-10, cis-12 CLA a
Page 53 and 54: Figure 2. 6. Trans-10, cis-12 CLA i
Page 55 and 56: Figure 2. 8. Trans-10, cis-12 CLA-i
Page 57 and 58: Discussion Feeding mixed CLA isomer
Page 59 and 60: in lipolysis may occur via an ERK-d
Page 61 and 62: espectively, by the MEK inhibitor U
Page 63 and 64: Furthermore, the CLA-mediated incre
Page 65 and 66: proteins. Inhibition of NFκB activ
Page 67 and 68: Sopasakis et al. 2004) and insulin
Page 69 and 70: antibodies for anti-glyceraldehydre
Page 71 and 72: pM of human insulin in the presence
Page 73 and 74: were (accession #NM000600) sense (5
Page 75 and 76: Transfection efficiency was examine
Page 77 and 78: 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 91 and 92: Figure 3. 6. Trans-10, cis-12 CLA-i
Page 93: Figure 3. 8. Specific depletion of
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 and 130: Figure 4. 8. Inhibitors of NFκB at
Page 131 and 132: Discussion Adipose tissue is a sour
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
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esearch topic I would like to exami
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Berg, A.H., Lin, Y., Lisanti, M.P.,
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Chen, C., Koh, A.J., Datta, N.S., Z
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Diradourian, C., Girard, J., and Pe
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Granlund, L., Juvet, L.K., Pedersen
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Imamura, M., Inoguchi, T., Ikuyama,
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Loscher, C.E., Draper, E., Leavy, O
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Piper, R.C., Hess, L.J., and James,
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Sinha, S., Perdomo, G., Brown, N.F.
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Vanden Berghe, W., Vermeulen, L., D
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