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Mechanisms by which conjugated linoleic acid causes human adipocyte delipidation

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Soonkyu Chung (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Michael K McIntosh

Abstract: "Obesity is an important health issue, having risen to epidemic proportions in the U.S. Use of conjugated linoleic acid (CLA), positional and geometric isomers of linoleic acid, has received recent attention due to its potential health benefits including the reduction of fat mass in animals. However, the effectiveness and safety of CLA consumption in humans remains unclear. Our group previously reported that trans-10, cis-12 CLA impaired the conversion of preadipocytes into lipid-filled adipocytes (e.g., differentiation) and caused adipocyte delipidation that involved inflammatory cytokines in a human cell model. However, the isomer-specific mechanism for these events was unknown. Thus, this research examined mechanisms by which trans-10, cis-12 CLA induced adipocyte delipidation, inflammation, and insulin resistance in primary cultures of human adipocytes. Delipidation of adipocytes by trans-10, cis-12 CLA was accompanied by increased lipolysis and changes in the morphology of lipid droplets and the expression and localization of proteins regulating lipid droplet metabolism. This process involved the translational control of adipose differentiated related protein (ADRP) through activation of mTOR/p70S6K/S6 signaling and transcriptional control of perilipin A. Prior to these morphological changes, it was shown that trans-10, cis-12 CLA promoted nuclear factor κB (NFκB) and mitogen activated protein kinase (MAPK) activation and subsequent induction of interleukin (IL)-6 which were, at least in part, responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator activated receptor gamma (PPAR)γ target gene expression and insulin sensitivity in human adipocytes. The essential role of NFκB on CLA-induced inflammation was confirmed by using RNA interference. Further studies were conducted examining the localization and characterization of the inflammatory response, including the type of cells involved, using lipopolysaccharide (LPS) as the inflammatory agent. It was demonstrated that LPS-induced, NFκB-dependent proinflammatory cytokine expression was predominantly from preadipocytes, which led to, at least in part, the suppression of PPAR activity and adipogenic gene expression and insulin sensitivity. Collectively, these data support the emerging concept that adipose tissue is a dynamic endocrine organ with the capacity to generate inflammatory signals that impact glucose and lipid metabolism. Furthermore, human preadipocytes have the capacity to generate these inflammatory signals induced by trans-10, cis-12 CLA and LPS, subsequently causing insulin resistance in neighboring adipocytes. These studies also revealed that NFκB- and MAPK-signaling mediate inflammation and insulin resistance induced by CLA and LPS. Thus, although the trans-10, cis-12 isomer of CLA may decrease the size and lipid content of human adipocytes, it may also cause insulin resistance, which is a hallmark of type 2 diabetes. "--Abstract from author supplied metadata.

Additional Information

Publication
Dissertation
Language: English
Date: 2006
Keywords
obesity, health, epidemic, United States, conjugated linoleic acid (CLA), geometric isomers, linoleic acid, adipocyte delipidation, inflammatory cytokines, human cell, lipopolysaccharide (LPS), proinflammatory cytokine expression, insulin, diabetes
Subjects
Fat cells--Growth--Molecular aspects
Adipose tissues
Linoleic acid
Inflammation