Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #134100
Title: TUMOR NECROSIS FACTOR-ALPHA STIMULATES LIPOLYSIS IN DIFFERENTIATED HUMAN ADIPOCYTES THROUGH ACTIVATION OF EXTRACELLULAR SIGNAL-RELATED KINASE AND ELEVATION OF INTRACELLULAR CAMP

Author
item ZHANG, HUI - HNRCA
item HALBLEIB, MELANIE - HNRCA
item MANGANIELLO, VINCENT - NIH
item GREENBERG, ANDREW - HNRCA

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2002
Publication Date: 10/1/2002
Citation: ZHANG, H.H., HALBLEIB, M., MANGANIELLO, V.C., GREENBERG, A.S. TUMOR NECROSIS FACTOR-ALPHA STIMULATES LIPOLYSIS IN DIFFERENTIATED HUMAN ADIPOCYTES THROUGH ACTIVATION OF EXTRACELLULAR SIGNAL-RELATED KINASE AND ELEVATION OF INTRACELLULAR CAMP. DIABETES. 2002.

Interpretive Summary: Obesity and type 2 diabetes are associated with increased concentrations of circulating free fatty acids (FFA) which are known to elicit insulin resistance. FFA in the blood is primarily dependent fat breakdown in fat cells. In obesity and type 2 diabetes fat cell breakdown continues unabated as fat cells accumulate more fat maintaining the amount of fat in the cell. A hormone called TNF is known to increase fat breakdown and higher amounts of TNF is found in fat cells of obese subjects. The increased levels of TNF may enhance fat breakdown releasing FFA and increasing its levels in the circulating blood of obese individuals. In light of the strong link between fat cell breakdown and insulin resistance, we investigated the mechanisms, by which TNF stimulates lipolysis, which to date is largely unknown. Our study demonstrates that TNF binds to fat cells and sends intracellular signals that cause fat breakdown. In this manuscript we define the intracellular signals which causes fat breakdown. Also we find that TNF decreases the expression of a protein in fat cells called, cyclic-nucleotide phosphodiesterase 3B, which set in motion the cellular signals which cause fat breakdown. Our findings are of significant importance because delineation of the mechanism(s) by which TNF-alpha increases fat breakdown may provide information for future development of preventative and therapeutic approaches to obesity-associated insulin resistance and diabetes.

Technical Abstract: Tumor necrosis factor-alpha (TNF-alpha) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-alpha increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK)-extracellular signal-related kinase (ERK) and elevation of intracellular cAMP. TNF-alpha activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-alpha treatment caused an electrophoretic shift of perilipin from 65 kDa to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent-protein kinase A (PKA). Co-incubation with TNF-alpha and MEK inhibitors caused perilipin to migrate as a single 65 kDa band. Consistent with the hypothesis that TNF-alpha induces perilipin hyperphosphorylation by activating PKA, TNF-alpha increased intracellular cAMP ~1.7 fold and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-alpha-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF- alpha induced lipolysis. Finally, TNF- alpha decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by ~50%, delineating a mechanism by which TNF-alpha could increase intracellular cAMP. Co-treatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-alpha stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP.