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

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Potential Metabolic Complications Associated with CLA Supplementation Even though trans-10, cis-12 CLA is effective in decreasing adiposity, most dietary supplements for human consumption contain a 1:1 ratio of cis-9, trans-11 CLA and trans-10, cis-12 CLA. Apart from the obvious health benefits observed from the animal studies using the mixed isomers of CLA, human studies indicate that some of these beneficial effects are considerably less evident, and are conflicting compared to animal studies (Blankson et al. 2000; Gaullier et al. 2005; Desroches et al.2005). Recently, several researchers have raised concerns about the potential safety of CLA. The concerns include the induction of fatty liver in animals (Clement et al. 2002), insulin resistance (reviewed in Brown and McIntosh 2003) and lipodystrophy (Riserus et al. 2004a, b), elevated markers of oxidative stress (Riserus et al. 2002), lipid peroxidation (Basu et al. 2000 a, b), enhanced C-reactive protein (Smedman et al. 2005), and impairment of endothelial function (Taylor et al. 2006). The possible deleterious effects of CLA intake appear to be due mainly to the trans-10, cis-12 isomer. Riserus et al. conducted (2001, 2002a,b, 2004a,b) a series of human clinical trials with each individual CLA isomer. Their data suggested that trans-10, cis-12 CLA enhanced risk profiles for people with the Metabolic Syndrome. These included unfavorable changes in serum lipid composition (i.e., elevated VLDL coupled with reduced HDL), hyperinsulinemia, impaired insulin sensitivity, resulting in increased risk of cardiovascular disease (Riserus et al. 2001, 2002a,b, 2004a,b). Furthermore, CLA may cause inflammation based on increase levels of serum C-reactive proteins (CRP) (Riserus et al. 2002; Smedman et al, 2005), a biomarker of inflammation. 11
In contrast, studies conducted in a number of animal and in vitro models suggested that CLA has anti-inflammatory and immune-ameliorating effects (Yu et al. 2002). However, only a limited number of CLA studies have been performed in humans. In addition to this paradoxal observation from Riserus’s group, Brown et al. (2004) reported that trans-10, cis-12 CLA induced proinflammatory cytokine secretions and insulin resistance in primary cultures of human adipocytes. Therefore, it is of particular interest to determine if CLA’s TG lowering actions are mediated by cytokine secretion and low- grade inflammation which are known to cause insulin resistance (reviewed in Wellen and Hotamisligil 2005). Insulin Resistance and Inflammation: Role of NFκB Insulin resistance is a characteristic feature of most cases of type 2 diabetes and is the defining pathophysiological defect in Metabolic Syndrome. An important recent development is the emergence of the concept that obesity is characterized by chronic low-grade inflammation. The potential relationships between inflammation and insulin resistance have been promoted by Hotamisligil and Spiegelman (Hotamisligil et al. 1993, 1994, 2003). Their earlier studies focused on production of tumor necrosis factor-α (TNF-α) and its ability to suppress insulin signaling mediated by the insulin receptor (IR) and insulin receptor substrates (IRSs). While the degree to which TNF-α itself mediates insulin resistance in human is controversial, findings by Hotamisligil’s group clearly defined the potential for insulin resistance to be caused by cross-talk between inflammatory (i.e., TNF-α) and metabolic (i.e., inactivation of IR or IRS) signalings. 12
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 and 8: I also would like to thank The Univ
Page 9 and 10: IV. PREADIPOCYTES MEDIATE LPS-INDUC
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: Figure 1. 2. Multiple mechanisms by
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
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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
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
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Figure 3. 8. Specific depletion of
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Figure 3. 10. Working model: Trans-
Page 97 and 98:
Based on our working model (Fig 3.1
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mRNA levels of TNF-α (Fig. 3). How
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humans (Riserus et al. 2004a), and
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most likely not impairing the diffe
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1) decreased adipogenic gene expres
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adipocytes from WAT in inflammation
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differentiation, cultures of SV cel
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Immunoblotting and 4MUrea-SDS-PAGE
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activity was measured using the Dua
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macrophages and myocytes, respectiv
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cultures, insulin’s stimulation o
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AD90 cultures treated with LPS. Con
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Table 4.1. List of human-gene speci
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Figure 4.2. Primary cultures of new
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Figure 4.4 LPS induction of cytokin
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Figure 4. 6. LPS suppresses PPARγ
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Figure 4. 8. Inhibitors of NFκB at
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Discussion Adipose tissue is a sour
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To determine if non-adipocytes othe
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attenuation of insulin sensitivity
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epression of NFκB target gene expr
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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
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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