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

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TABLE OF CONTENTS vi Page LIST OF TABLES……………………………………………………………………...viii LST OF FIGURES…………………………………………………………………….…ix CHAPTER I. INTRODUCTION…………………………………………………………1 Overview…………………………………………………………......1 Background and Significance………......…………………………...3 Historical Review of CLA…………………………………….3 Anti-adipogenic <strong>Mechanisms</strong> of CLA……………………….6 Potential Metabolic Cmplications Associated with CLA Supplementation……………………………………………..11 Insulin Resistance and Inflammation: Role of NFκB………..12 Central Hypothesis and Specific Objectives………………………16 II. TRANS-10, CIS-12 CLA INCREASES ADIPOCYTE LIPOLYSIS AND ALTERS LIPID DROPLET-ASSOCIATED PROTEINS: ROLE OF mTOR AND ERK SIGNALING……………………..….…18 Abstract…………………………………………………………….18 Introduction………………………………………………………...19 Materials and Methods……………………………………………..22 Results ……………………………………………………………26 Discussion………………………………………………………….44 III. CONJUGATED LINOLEIC ACID PROMOTES HUMAN ADIPOCYTE INSULIN RESISTANCE THROUGH NFκB- DEPENDENT CYTOKINE PRODUCTION…………………..…….51 Abstract…………………………………………………………….51 Introduction………………………………………………………...52 Materials and Methods……………………………………………..55 Results ……………………………………………………………62 Discussion………………………………………………………….83
IV. PREADIPOCYTES MEDIATE LPS-INDUCED INFLAMMATION AND INSULIN RESISTANCE IN PRIMARY CULTURES OF NEWLY DIFFERENTIATED HUMAN ADIPOCYTES………...……. 91 Abstract…………………………………………………………….91 Introduction………………………………………………………...92 Materials and Methods……………………………………………..94 Results …………………………………………………………100 Discussion……………………………………………………….118 EPILOGUE…………………………………………………….……………….............126 BIBLIOGRAPHY………………………………………………………………….....133 vii
Page 1 and 2: CHUNG, SOONKYU, Ph. D. Mechanisms b
Page 3 and 4: MECHANISMS BY WHICH CONJUGATED LINO
Page 5 and 6: APPROVAL PAGE This Dissertation has
Page 7: I also would like to thank The Univ
Page 11 and 12: LIST OF FIGURES ix Page Figure 1.1.
Page 13 and 14: Figure 4.7. LPS-induced NFκB activ
Page 15 and 16: in animals and some humans (reviewe
Page 17 and 18: CLA is potentially effective in: 1)
Page 19 and 20: Anti-adipogenic Mechanisms of CLA T
Page 21 and 22: 2005). Chapter II of this dissertat
Page 23 and 24: Figure 1. 2. Multiple mechanisms by
Page 25 and 26: In contrast, studies conducted in a
Page 27 and 28: activation. Similarly, Chen et al.
Page 29 and 30: Central Hypothesis and Specific Obj
Page 31 and 32: CHAPTER II TRANS-10, CIS-12 CLA INC
Page 33 and 34: of MEK/ERK signaling by trans-10, c
Page 35 and 36: Materials and Methods Materials All
Page 37 and 38: the cultures for additional 12 h. A
Page 39 and 40: precipitated with ethanol, dried, a
Page 41 and 42: 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 51 and 52: Figure 2. 4. 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 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 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
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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