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

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ole of chronic ERK activation by CLA, the silencing of ERK using RNA interference followed by the examination of signaling cascade would be good strategy to take. Polyunsaturated fatty acids are known to play an anti-inflammatory role. Parallel to this concept, it is suggested recently that docosahexaenoic acid (DHA) supplementation to the diet can attenuate CLA-induced fatty liver through the reduction of hepatic fatty acid synthesis without affecting adipokine production in C57BL/6N mice (Yanagita et al. 2005). In chapter III, I have proposed that inflammation contributes to adipocytes delipidation by CLA, but there is a possibility the two pathways (i.e., inflammation and delipidation) are regulated in a distinct manner. Taking advantage of anti-inflammatory properties of fish oil, attenuation of adiposity by CLA without triggering inflammation might be achievable by co-supplementation with DHA. My research questions focused on inflammation, and its impact on insulin resistance and type II diabetes. In the future, I would like to investigate potential factors secreted from visceral fat comparing to subcutaneous fat that promote insulin resistance in response to inflammatory stimuli. Recently, visfatin has been identified as an adipokine, which is predominantly secreted from visceral adipose tissue both in humans and mice. Visceral and subcutaneous adipose tissue display important metabolic differences that underlie the association of visceral obesity with obesity-related cardiovascular and metabolic alterations. Therefore, research revealing the association of visfatin to insulin resistance, and its mechanism of action offer promising data that could potentially provide insights about why visceral adipose tissue is a more important predictor of insulin resistance compare to subcutaneous adipose tissue. Another future 131
esearch topic I would like to examine is systemic regulation of inflammation. I have performed exciting experiments using human adipocyte cultures to explore the dynamics of CLA-induced signaling pathway mediating delipidation. However, cellular level research is limited its scope and dose not allow for understanding systemic responses to inflammation. Thus, studies using knockout animal would provide more global and physiological insights about critical clues that we would enhance our comprehension about the interrelation between obesity-induced adipocyte inflammation and diabetes, cardiovascular disease, and liver and islet dysfunction. Insights obtained from the research reported in this dissertation and the proposed future research would have a potential to lead to novel investigations and therapeutic approaches that may improve our understating of Metabolic Syndrome. 132
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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. 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
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myotubes (Sinha et al. 2004; Weiger
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controls was found in cytosol (Fig
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Depletion of NFκB p65 by RNAi Atte
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eports of cytokine-mediated insulin
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Figure 3. 2. Trans-10, cis-12 CLA i
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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: Concerning membrane specific recept
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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