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

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
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