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The Function of c-Jun NH2-Terminal Kinases in Lipid Metabolism and Adipocyte Function

Andrea Veronica Rozo
B.S. Biological Sciences
B.S. Nutritional Sciences
Rutgers University, Cook College - 2004
New Brunswick, NJ

Thesis Advisor: Harvey Weiss, Ph.D.
Graduate Program in Physiology & Integrative Biology

School of Public Health Conference Room 258
Piscataway, NJ

Thursday, August 26, 2010
10:00 a.m.


Elevated plasma level of free fatty acid (FFA) inhibits insulin signaling. In adipose tissue during obesity, FFAs activate c-Jun NH2-Terminal kinases (JNK) impairing insulin sensitivity and adipocyte function. Plasma FFA level is determined primarily by the hydrolysis of adipocyte triacylglycerol (TAG) and FFA re-esterification. Stable cell lines, using shRNA mediated gene ablation to produce 3T3-L1 adipocytes deficient in JNK1, JNK2 or both, were established. Using this system, the details of the function of JNK in the regulation of adipocyte gene expression and lipid metabolism were determined.
Microarray analysis showed that JNK-deficiency enhanced the expression of several gene subsets, including those involved in TAG synthesis and FFA re-esterification and release, supporting a role for JNK in regulating adipocyte specific gene expression. JNK1/JNK2 deficient adipocytes released more glycerol than JNK control cells, indicating elevated basal TAG hydrolysis, with no change in glycerol release in adipocytes deficient in only one JNK subtype. Interestingly, all JNK-deficient adipocytes released less FFA than JNK-intact adipocytes, suggesting that JNK subtypes function redundantly to regulate basal TAG hydrolysis, but function independently to regulate FFA release.
FFA not released after TAG hydrolysis from JNK-deficient adipocytes was primarily retained in TAG, implying elevated FFA recycling. FFA release in the presence of the TAG synthesis inhibitor, Triacsin C, was restored in JNK-deficient adipocytes, further supporting a role for JNK in FFA recycling. PEPCK, a key regulator of glyceroneogenesis, was tested as a potential mechanism for enhanced FFA retention given its elevated expression and activity in JNK-deficiency. In the presence of a PEPCK inhibitor, FFA release was unchanged and failed to support a role for PEPCK in mediating increased FFA retention. However, measurements of total cellular TAG showed elevated TAG content in JNK-deficiency suggesting enhanced activity of the TAG synthesis pathways, independent of PEPCK. Taken together, these data indicate a crucial and tissue specific role for JNK in a regulating the breakdown and synthesis of TAG and FFA release. Thus, it is important to identify the intrinsic roles of JNK in the regulation of adipocyte function, focusing on lipolysis, FFA release and re-esterification, which are critical to systemic insulin sensitivity.

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