Cellular and Molecular Mechanisms Involved in the Induction of the Lipostatic Cytokine Leptin by Tumor Necrosis Factor Alpha

The proper regulation of body weight in humans is remarkably important to our well-being. For instance, obesity is a major health concern since cardiovascular, neoplastic and metabolic diseases occur with much greater frequency in the obese. Conversely, the inappropriate loss of body mass in cachexia contributes to the morbidity and mortality of chronic disease. Leptin is a protein hormone secreted by adipocytes that has been identified as a blood-borne factor inherently linking feeding behavior and metabolism to the individual's nutritional state. The studies detailed herein examine hyperleptinemia elicited by tumor necrosis factor (TNF) alpha at many levels. Initial studies determined that TNFalpha could act directly on adipocytes to stimulate increased leptin secretion through the p55 TNF receptor (TNFR). This was an important first step, since it allowed us to identify potential intracellular signaling pathways activated by the p55 TNFR that might lead to leptin gene expression. Subsequent studies found that a highly specific inhibitor of p38 mitogen-activated protein kinase (MAPK) could abrogate TNFalpha-induced leptin gene expression. This may be mediated through the ability of p38 MAPK to phosphorylate and activate CCAAT/enhancer binding protein (C/EBP), because inhibiting p38 MAPK blocked both leptin expression and prevented the increase in C/EBP nuclear translocation that was stimulated by TNFalpha treatment. Finally, it was found that pretreatment with peroxisome proliferator-activated receptor ligands could significantly ameliorate inflammatory hyperleptinemia without affecting proinflammatory cytokine production or C/EBP nuclear translocation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Finck, Brian Neal

Contributors dc:contributor

• Johnson, Rodney W.

• Biology, Molecular

Language dc:language

eng

Identifier

(MiAaPQ)AAI9971075

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/83662