Development of obesity-induced inflammation and insulin resistance: The role of adipose tissue, fatty acids, and toll-like receptors

dc.contributor.advisor Michael E. Spurlock
dc.contributor.author Davis, Jeremy
dc.contributor.department Food Science and Human Nutrition
dc.date 2018-08-11T12:45:30.000
dc.date.accessioned 2020-06-30T02:33:47Z
dc.date.available 2020-06-30T02:33:47Z
dc.date.copyright Tue Jan 01 00:00:00 UTC 2008
dc.date.embargo 2013-06-05
dc.date.issued 2008-01-01
dc.description.abstract <p>The innate immune receptors, toll-like receptor-2 (Tlr2) and toll-like receptor-4 (Tlr4), are implicated in the development of inflammation and insulin resistance in various cell populations. However, little is known about the relationship of these receptors in dietinduced obesity (DIO). We have shown that Tlr4 deficient C57BL/10ScN mice were protected against DIO, specifically when mice were fed a high saturated fatty acid (SFA) diet. Moreover, these mice exhibited a specific reduction in adipose tissue (AT) inflammation as evidenced by the reduction in nuclear factor kappa B (NFkB) activation, proinflammatory gene expression, and macrophage accumulation. There was also a marked increase in Tlr2 expression in mice fed a high fat diet. 3T3-L1 adipocytes treated with the Tlr2 agonist, zymosan A (ZymA), exhibited increased NFkB and activator protein-1 (AP-1) activation, proinflammatory gene expression, reactive oxygen species (ROS) accumulation, and insulin resistance, similarly to palmitate or Tlr4 agonist lipopolysaccharide (LPS). These effects were attenuated in adipocytes treated with a specific c-jun N-terminal kinase (JNK) inhibitor (SP600125) indicating involvement of this intracellular kinase in SFA and Tlr agonistmediated signaling. Finally, we demonstrated that Tlr2-/- mice were also protected from DIO. However, unlike Tlr4 deficient 10ScN mice there were no significant changes in body weight, energy intake, or lipid profile. Inflammatory and oxidative stress markers in serum</p> <p>(C-reactive protein (CRP), endotoxin, and monocyte chemoattractant protein-1(MCP-1)) and AT (Tumor necrosis factor; (TNF), interleukin-6 (IL-6), MCP-1, F4/80, and nitric oxide synthase-2 (NOS2) transcript abundance) were attenuated in Tlr2-/- and 10ScN mice, which was more apparent in mice fed high SFA diet. Insulin sensitivity was improved in 10ScN, but not Tlr2-/- mice. However, stromal vascular (SV) cells isolated from AT of Tlr2-/- mice had a marked increase in insulin sensitivity, demonstrating the potential involvement of Tlr2 in obesity-induced insulin resistance in AT. Based on these studies, Tlr2 and Tlr4 may represent ideal targets for pharmaceutical, as well as dietary, interventions designed to attenuate obesity and related co-morbidities, including Type 2 diabetes mellitus (DM) and cardiovascular disease (CVD).</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/etd/11169/
dc.identifier.articleid 2202
dc.identifier.contextkey 2807400
dc.identifier.doi https://doi.org/10.31274/etd-180810-1101
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath etd/11169
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/25375
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/etd/11169/Davis_iastate_0097E_10130.pdf|||Fri Jan 14 18:43:54 UTC 2022
dc.subject.disciplines Nutrition
dc.subject.keywords Adipose Tissue
dc.subject.keywords Diabetes
dc.subject.keywords Inflammation
dc.subject.keywords Obesity
dc.subject.keywords Toll-like Receptors
dc.title Development of obesity-induced inflammation and insulin resistance: The role of adipose tissue, fatty acids, and toll-like receptors
dc.type article
dc.type.genre dissertation
dspace.entity.type Publication
relation.isOrgUnitOfPublication 4b6428c6-1fda-4a40-b375-456d49d2fb80
thesis.degree.level dissertation
thesis.degree.name Doctor of Philosophy
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