Show simple item record

dc.contributor.authorMcMillan, Ryan P.en_US
dc.date.accessioned2014-03-14T21:15:29Z
dc.date.available2014-03-14T21:15:29Z
dc.date.issued2009-06-25en_US
dc.identifier.otheretd-07082009-205233en_US
dc.identifier.urihttp://hdl.handle.net/10919/38698
dc.description.abstractGrowing evidence suggests that obesity and associated metabolic dysregulation occurs in concert with chronic low-grade inflammation. Toll-like receptors (TLR) are transmembrane receptors that play an important role in innate immunity and the induction of inflammatory responses. Our laboratory has observed that TLR4 expression is elevated in the skeletal muscle of obese humans and is associated with reduced fatty acid (FA) oxidation and increased lipid synthesis. Additionally, activation of this pathway by lipopolysaccharide (LPS), ex vivo, results in a shift in substrate metabolism favoring glucose as an energy substrate and preferential storage of FA in intracellular lipid depots. The purpose of this study was to examine the effects of saturated vs. monounsaturated FA on TLR4 transcription and signaling using ex vivo and in vivo models. C2C12 myotubes were incubated in FA-enriched growth medium with varying ratios of palmitate and oleate for 12 hours. Following FA treatment, cells were either collected for measures of mRNA and protein levels of TLR4 or challenged with LPS (500 ng/mL) for 2 hours to assess TLR4 mediated changes in interleukin-6 (IL-6) and glucose and fatty acid metabolism. TLR4 mRNA and protein content were increased in stepwise fashion with higher palmitate concentration (p<0.05). This was associated with an exacerbated LPS effect on IL-6 mRNA and protein levels, and glucose and fatty acid metabolism. To determine if these effects are translated to an in-vivo model, C57BL/6 mice were fed high saturated fat (HSF), high monounsaturated fat (HMF), and control diets for 10 weeks. Following the dietary intervention, animals were challenged with I.P. injections of either saline or LPS (~25μg/mouse), sacrificed 4 hours post-injection, and red and white gastrocnemius muscle were harvested for measures of expression and protein levels of TLR4 and IL-6, and glucose and fatty acid metabolism. TLR4 mRNA and protein levels were not altered with either the HSF or HMF diets. However, there was a heightened LPS response with regards to increases in IL-6 and TNF-α, and enhanced shifts in substrate metabolism following the HSF diet (p<0.05). These effects were not observed in response to the HMF diet. In conclusion, these data demonstrate that a milieu of high saturated fatty acids results in elevated sensitization of the TLR4 pathway in skeletal muscle. These results provide insight into how a westernized diet, one enriched in saturated fat, may link chronic inflammation with obesity-associated metabolic abnormalities.en_US
dc.publisherVirginia Techen_US
dc.relation.haspartETD_McMillan.pdfen_US
dc.relation.haspartETD-McMillan.pdfen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjecttoll-like receptor 4en_US
dc.subjectinflammationen_US
dc.subjectskeletal muscleen_US
dc.subjectsaturated fatty acidsen_US
dc.subjectmonounsaturated fatty acidsen_US
dc.titleThe Role of Fatty Acids on Toll-like Receptor 4 Regulation of Substrate Metabolism with Obesityen_US
dc.typeDissertationen_US
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen_US
dc.contributor.committeechairHulver, Matthew Wadeen_US
dc.contributor.committeememberGood, Deborah J.en_US
dc.contributor.committeememberDavy, Kevin P.en_US
dc.contributor.committeememberGrange, Robert W.en_US
dc.contributor.committeememberLi, Liwuen_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07082009-205233/en_US
dc.date.sdate2009-07-08en_US
dc.date.rdate2009-08-04
dc.date.adate2009-08-04en_US


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record